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Genetic variations in cytotoxic T-lymphocyte antigen-4 and susceptibility to cervical cancer
Abstract
Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a molecule expressed predominantly on activated T cells, plays an important role in the down-regulation of T-cell activation. A case-control study was conducted in Han women living in Southeast China to evaluate the potential effects of CTLA-4 gene polymorphisms on susceptibility to cervical cancer. We genotyped polymorphisms in CTLA-4 (-318T/C, CT60 G/A, +49G/A, -658T/C, and -1661G/A) and calculated odds ratios for the genotype and allele distributions between patients and controls, in order to assess the association between CTLA-4 genotypes and cancer risk. We then examined the functional relevance of the polymorphisms using enzyme-linked immunosorbent assays (ELISAs), in vitro lymphocyte proliferation assay, and cytotoxic assay. The CTLA-4 -318 CC, CT60 AA, and +49 GG genotype frequencies were lower in patients than in controls (p<0.05). The frequencies of CTLA-4 -318T allele and CT60G allele carriers were significantly higher in patients than in controls (p<0.05). No significant differences were found in the genotype and allele frequencies in -658T/C, and -1661G/A between patients and healthy controls (p>0.05). Upon stimulation, peripheral blood mononuclear cells (PBMCs) carrying the -318TT and CT60GG genotypes exhibited significantly lower proliferation, IL-2, and IL-4 levels; fewer cytolytic activities; and higher TGF-β levels compared with PBMCs carrying the -318 CC/CT or CT60 AA/AG genotypes. We also found that CTLA-4 -318T/C and CT60 G/A single nucleotide polymorphisms were associated with the severity of cervical cancer. These results indicate that CTLA-4 -318T/C and CT60 G/A can affect cervical cancer susceptibility by altering the immune status of an individual.
... allele is associated with higher expression of CTLA-4, and therefore, may increase a risk of cancer development and progression. Xiong and colleagues (37) investigated functional relevance of CTLA-4c.-319C>T and found that upon stimulation PBMCs derived from subjects with CTLA-4c.-319 T/T genotype had significantly lower proliferation ability, produced lower levels of IL-2 and IL-4, but on the contrary higher levels of TGF-b compared with PBMCs derived from subjects with CTLA-4c.-319 ...
... The authors concluded, that the carriers of CTLA-4c.-319*T allele "have stronger negative regulation of T-cell proliferation and function, which might be the underlying mechanisms conferring cervical cancer susceptibility" (37). ...
... Xiong and colleagues (37) in work described above investigated also functional relevance of CTLA-4CT60G>A SNP and observed the same functional effects for the CTLA-4CT60*G allele as for CTLA-4c.-319*T allele (37). On the other hand, the CTLA-4CT60 A/A genotype was associated with the approximately 40% increase in T reg frequency in the peripheral blood (PB) of healthy donors (40). ...
In recent years, immunotherapy has been revolutionized by a new approach that works by blocking receptors called immune checkpoints (IC). These molecules play a key role in maintaining immune homeostasis, mainly by suppressing the immune response and by preventing its overactivation. Since inhibition of the immune response by IC can be used by cancer to avoid recognition and destruction by immune system, blocking them enhances the anti-tumor response. This therapeutic approach has brought spectacular clinical effects. The ICs present heterogeneous expression patterns on immune cells, which may affect the effectiveness of immunotherapy. The inherited genetic variants in regulatory regions of ICs genes can be considered as potential factors responsible for observed inter-individual differences in ICs expression levels on immune cells. Additionally, polymorphism located in exons may introduce changes to ICs amino acid sequences with potential impact on functional properties of these molecules. Since genetic variants may affect both expression and structure of ICs, they are considered as risk factors of cancer development. Inherited genetic markers such as SNPs may also be useful in stratification patients into groups which will benefit from particular immunotherapy. In this review, we have comprehensively summarized the current understanding of the relationship between inherited variations of CTLA-4, PDCD1 , PD-L1, BTLA , TIM-3 , and LAG-3 genes in order to select SNPs which can be used as predictive biomarkers in personalized evaluation of cancer risk development and outcomes as well as possible response to immunotherapy.
... The CTLA-4 gene, located on chromosome2 at band q33, plays an important role in the deregulation of T-lymphocyte effector cells [32,33]. There is evidence of multiple polymorphisms in CTLA-4 associated with susceptibility to autoimmune diseases [34,35] and multiple single nucleotide polymorphisms (SNPs) in the coding region of CTLA-4 related to susceptibility to human tumors (renal cancer, breast cancer, melanoma, gastric cancer) [36,37]. ...
... There is evidence of multiple polymorphisms in CTLA-4 associated with susceptibility to autoimmune diseases [34,35] and multiple single nucleotide polymorphisms (SNPs) in the coding region of CTLA-4 related to susceptibility to human tumors (renal cancer, breast cancer, melanoma, gastric cancer) [36,37]. It has been shown that in Chinese women positive for HPV, the CTLA-4 -318 C/T and CTLA-4 CT60 G/A SNPs affect the development of CC [32]. Although there is no clarity with respect to how the CTLA-4 polymorphisms trigger the neoplasia, its causes include the loss of homeostasis of the immune system [32], activation of the cytokine pathway [32] and the overexpression of CTLA-4; the latter may trigger inhibition of the immune activity of T cells in the presence of certain alleles [38]. ...
... It has been shown that in Chinese women positive for HPV, the CTLA-4 -318 C/T and CTLA-4 CT60 G/A SNPs affect the development of CC [32]. Although there is no clarity with respect to how the CTLA-4 polymorphisms trigger the neoplasia, its causes include the loss of homeostasis of the immune system [32], activation of the cytokine pathway [32] and the overexpression of CTLA-4; the latter may trigger inhibition of the immune activity of T cells in the presence of certain alleles [38]. ...
... Based on the above selection criteria, a total of 67 eligible studies were included in the current meta-analysis. For rs231775, 64 studies involved a total of 23617 cases and 27261 controls [10][11][12][13][14][15]. Moreover, there were 30 studies with 9675 cases and 9623 controls for rs3087243 [12-15, 17, 20, 23-25, 27-29, 31, 32, 35, 37, 40, 41, 44, 45, 47, 53, 54, 61, 63, 65, 66, 73-75]. ...
... Moreover, there were 30 studies with 9675 cases and 9623 controls for rs3087243 [12-15, 17, 20, 23-25, 27-29, 31, 32, 35, 37, 40, 41, 44, 45, 47, 53, 54, 61, 63, 65, 66, 73-75]. Additionally, rs4553808 was in 17 studies [12,14,15,23,28,29,31,37,41,44,47,49,51,52,62,73,76], rs5742909 was in 32 studies [12, 14, 15, 20, 21, 24, 25, 28-30, 32, 34, 35, 39-41, 45, 47, 52-54, 56, 57, 59, 62, 63, 65, 66, 70, 73, 76, 77], rs733618 was in 14 studies [13,23,28,37,44,47,51,52,62,[73][74][75][76]78], and they were analysed. Of the 67 studies, 9 presented a significant deviation from HWE (5 studies on rs231775 [11, 16). ...
Background/aims:
CTLA-4 polymorphisms are associated with susceptibility to various cancers, but the results are often conflicting. Hence, we performed a comprehensive meta-analysis to quantitatively investigate the association between CTLA-4 polymorphisms (rs231775, rs4553808，rs5742909, rs3087243 or rs733618) and cancer risk.
Methods:
Data were collected from PubMed and Web of Science. A total of 67 case-control studies were selected for quantitative analysis. Stata (Version 12) software was used to calculate the odds ratio (OR) and 95% confidence interval (CI) to evaluate the strength of the associations. Subgroup meta-analysis was conducted based on ethnicity and cancer type. Heterogeneity tests, sensitivity analysis, and publication bias assessments were also performed.
Results:
rs231775, rs4553808 and rs5742909 but not rs3087243 and rs733618 were significantly related to cancer risk. In analyses stratified by ethnicity, both rs231775 and rs4553808 were significant susceptibility polymorphisms in an Asian population but not in a Caucasian population. Moreover, there were stronger associations between the rs231775 polymorphism and increased risk of bone, breast, liver, head and neck and pancreatic cancers. Additionally, rs4553808 was associated with significantly increased susceptibility to breast cancer and head and neck cancer.
Conclusion:
rs231775, rs4553808 and rs5742909 may be used as predictive genetic biomarkers for cancer predisposition. Combined detection of CTLA-4 SNPs could be a useful tool for prediction of cancer susceptibility in clinical practice.
... CTLA-4 polymorphisms have been demonstrated to be associated with increased susceptibility to various malignant tumors in a number of different ethnic populations. Previous studies have been performed to determine whether the -318 cytosine/thymine (-318C/T) polymorphism was involved in the etiology of various malignant tumors in Asian population (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). However, the results from these studies remain inconclusive and conflicting. ...
... Case Control First author CC TC TT C T CC TC TT C T Refs. Cheng 59 3 0 121 3 209 40 1 Thus, 20 articles with a total of 3,539 cases and 4,690 controls were included in the final data extraction (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). There were two articles that analyzed two cancer types (colorectal cancer and gastric cancer) using the same control group (11,12). ...
The cytotoxic T-lymphocyte antigen 4 (CTLA-4) polymorphic loci -318 cytosine/thymine (-318C/T) has been previously implicated in malignant tumor susceptibility. However, there were no precise conclusions about the correlation, the results from published studies were inconclusive. The aim of the current meta-analysis was to investigate the associations between CTLA-4 -318C/T polymorphisms and risk of malignant tumors in Asian population. We conducted a search in PubMed, Embase, the Chinese Journals Full-Text Database, Chinese Biomedical Database, and the Wanfang database. All studies were published up to September 30, 2015. Two reviewers analysed the data independently. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. In total, 20 case-controlled studies with 3,539 cases and 4,690 controls were included in the final meta-analysis. The overall estimation demonstrated a significant association between CTLA-4 -318C/T polymorphism and malignant tumor risk in the Asian populations (TT+TC vs. CC: OR, 1.28; 95% CI, 1.07-1.53. TT vs. TC+CC: OR, 1.43; 95% CI, 1.03-1.99; TT vs. CC: OR, 1.51; 95% CI, 1.09-2.10. TC vs. CC: OR, 1.26; 95% CI, 1.06-1.50. T vs. C: OR, 1.25, 95% CI, 1.05-1.47). In the subgroup analysis by countries, we found that the dominant model (TT+TC vs. CC) revealed an increased risk of developing malignant tumors in the Chinese study population (OR, 1.41; 95% CI, 1.13-1.76), but no association was demonstrated in the other countries. The current meta-analysis suggests that CTLA-4 -318C/T polymorphism is significantly associated with the risk of malignance tumors in Asian populations, especially in those from China. Further studies for additional Asian countries are required to further evaluate the association.
... According to study performed by Fang M in 2018 showed that, rs4553808 was associated with significantly increased susceptibility to breast cancer and head and neck cancer (24) . Many studies confirmed role of rs4553808 with many type of human cancer, sporadic breast cancer in Chinese Han population (25) , cervical cancer (26) , breast cancer (27) and another disease.CTLA-4 haplotypes are important determinant of HBV recovery, haplotypes containing the +49G allele either alone or with -1722 were associated with clearance of HBV infection. Since these haplotypes may alter the ability of CTLA-4 to down regulate the immune response (2) . ...
Abstract The cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory receptors expressed transiently on CD4+ and CD8+ T cell and constitutively on CD4+CD25+ T-regulator (T-reg) cells. CTLA-4 gene encoded two different protein forms: soluble CTLA-4 (sCTLA-4) and full length CTLA-4 (flCTLA-4). Treg cells were demonstrated to be a prominent source of sCTLA-4.Single nucleotide polymorphisms (SNPs) occurring on the CTLA-4 gene can modify the ability to control the proliferation of T-lymphocytes, thereby impacting the persistence or progression of chronic hepatitis B (HBV) infections.The present study aimed to determine whether the polymorphisms in CTLA-4gene, (CTLA-4-1722T/Crs733618, CTLA-4-319C/T rs5742909and CTLA-4-1661A/G rs4553808) are associated with the progression or persistence of chronic HBV, and the impact of sCTLA-4 on chronic HBV disease in Iraq.Ninety patients with chronic (complicated and uncomplicated) HBV and 30 healthy control were recruited. A blood sample and genomic DNA were collected from all patients, the sCTLA-4 in patients and healthy control are detected by ELISA assay. The CTLA-4- gene was detected by DNA sequencing after amplification of the genes by Conventional PCR with specific primers.All the genotypes for CTLA-4 polymorphisms were analyzed for linkage disequilibrium. There was very high linkage disequilibrium between rs4553808 with rs733618, and in moderate LD with rs420909 suggesting that alleles of these SNPs variants are likely to be inherited together.
... Finally, 11 case-control studies considering 3899 cases and 4608 controls were included in the metaanalysis. [10,17,[19][20][21][22][23][24][25][26][27] The publication years of the assessed studies ranged from 2007 to 2018. Of these, there were 3 studies of Caucasian descendants and 8 studies of Asian descendants. ...
Background:
Number of studies have been performed to evaluate the relationship between the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) gene variant rs5742909 polymorphism and cervical cancer risk, but the sample size was small and the results were conflicting. This meta-analysis was conducted to comprehensively evaluate the overall association.
Methods:
PubMed, Web of Science, Embase, China Biology Medical Literature database, China National Knowledge Infrastructure, WanFang, and Weipu databases were searched before July 31, 2018. The strength of associations was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were conducted using Review Manager 5.3 and Stata 14.0.
Results:
Eleven studies involved 3899 cases and 4608 controls. Overall, significant association was observed between the CTLA-4 gene variant rs5742909 polymorphism and cervical cancer (T vs C: OR = 1.40, 95% CI = 1.12-1.76; TT vs CC: OR = 2.22, 95% CI = 1.13-4.37; TT vs CT+CC: OR = 1.96, 95% CI = 1.03-3.74; TT+CT vs CC: OR = 1.47, 95% CI = 1.14-1.90). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (T vs C: OR = 1.56, 95% CI = 1.22-1.99), but not in Caucasians (T vs C: OR = 1.19, 95% CI = 0.87-1.62). The sensitivity analysis confirmed the reliability and stability of the meta-analysis.
Conclusion:
our meta-analysis supports that the CTLA-4 gene variant rs5742909 polymorphism might contribute to individual susceptibility to cervical cancer in Asians.
... 22 CTLA-4 is polymorphic, and several important SNPs in CTLA-4 have been reported to be associated with a range of different malignancies. [23][24][25] Although a large number of studies suggest that +49 G/A polymorphism in CTLA-4 is significantly associated with HCC, only few studies have been conducted to investigate the associations between −318 T/C, CT60 G/A variants and HCC risk. Thus, we performed a comprehensive case-control study to explore the association of CTLA-4 −318 T/C and CT60 G/A polymorphisms with HCC risk in a Chinese Han population. ...
Our aim was to evaluate the association of genetic polymorhisms of immunoregulatory molecules with susceptibility to hepatocellular carcinoma (HCC). The polymorphisms in CTLA‐4 (‐318 T/C, CT60 G/A), TNF (‐238 G/A, ‐308 G/A) and IL10 (‐592 C/A, ‐819 C/T) were genotyped by PCR and DNA sequencing. The functional relevance of the polymorphisms was examined by ELISAs, in vitro lymphocyte proliferation assay, and cytotoxic assay. The CTLA‐4 ‐318 TC/TT, CTLA‐4 CT60 GG, IL10 ‐592 CA and ‐819 CT/TT variants, CTLA‐4 ‐318 T and IL 10 ‐819 T alleles were positively associated with HCC risk (p<0.05). While TNF ‐238 AA variant, TNF ‐238 A allele were associated with decreased risk of HCC (p<0.05). Furthermore, combinations of CTLA‐4 ‐318 TC/TT and TNF ‐238 GG/GA; CTLA‐4 ‐318 TC/TT and IL 10 ‐819 CC; CTLA‐4 ‐318 CC and IL 10 ‐819 CT/TT in HCC patients were statistically significant (p<0.05). Peripheral blood mononuclear cells (PBMCs) carrying ‐318 TC/TT genotypes exhibited significantly lower proliferation rates, decreased IL‐2, IL‐4 levels, fewer cytolytic activities, and elevated TGF‐β levels. For IL 10 ‐819 C/T, the CC genotype was significantly associated with higher proliferation rate, decreased TGF‐β, IL‐10 levels and higher cytolytic activities (p<0.05). For TNF ‐238 G/A, the AA genotype only had association with serum IL‐2, IL‐4 (p<0.05). In addition, we also found that CTLA‐4 ‐318 T/C, IL‐10 ‐819 T/C variants, combinations of CTLA‐4 ‐318 CC with IL 10 ‐819 CT or TT, CTLA‐4 ‐318 TC or TT with IL 10 ‐819 CT or TT were associated with the severity of HCC. These findings suggest that CTLA‐4 ‐318 TC/TT, IL 10 ‐819 CT/TT could promote the pathogenesis of HCC, which might be related with down‐regulation of Th1/Th2‐type cytokines, and/or up‐regulation of Th3‐type cytokines. This article is protected by copyright. All rights reserved.
... Several molecular epidemiological studies have focused on evaluation of the association between the CT60 SNP and various cancers, but the obtained results differ depending on the population and the type of cancer. The CT60[G] allele was found to be the risk allele for sporadic breast cancer (17,32), multiple myeloma (10), thymoma (33) and for cervical cancer (34). The same allele was found to be protective for skin cancer (35). ...
... Several molecular epidemiological studies have focused on evaluation of the association between the CT60 SNP and various cancers, but the obtained results differ depending on the population and the type of cancer. The CT60[G] allele was found to be the risk allele for sporadic breast cancer (17,32), multiple myeloma (10), thymoma (33) and for cervical cancer (34). The same allele was found to be protective for skin cancer (35). ...
Polymorphisms in co-stimulatory genes are associated with susceptibility to several malignances such as breast cancer, cervical cancer and chronic lymphocytic leukemia, but have been scarcely investigated in renal cell cancer (RCC). A total of 310 RCC patients and 518 controls were genotyped for single-nucleotide polymorphisms (SNPs) in the CTLA-4 and CD28 genes: CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*6230G>A (CT60; rs3087243), CTLA-4g.*10223G>T (Jo31; rs11571302), CD28c.17+3T>C (rs3116496) and CD28c.-1042G>A (rs3181098). The distribution of the alleles, genotypes and haplotypes in the CTLA-4 and CD28 genes were similar in the RCC patients and in the controls. However, among the patients with a clear cell RCC (CCRCC), the G allele carriers of CT60 and Jo31 SNPs were overrepresented, and the overrepresentation became significant for the carriers of CT60[G] allele in CCRCC patients with necrosis in the primary tumor (P = 0.046). The CTLA-4c.49A>G[A]/CTLA-4g.319C>T[C]/CT60[A]/Jo31[T]/CD28c.17+3T>C[T]/ CD28c.1042G>A[G] haplotype was associated with an approximately threefold increased risk of primary tumor necrosis in CCRCC patients (Pcorrected = 0.0000007) and with the advanced stage of disease (IV) (Pcorrected = 0.001). When stratified by gender, CD28c.-1042G>A[GG] genotype was more frequent in the female CCRCC patients compared with healthy women (P = 0.042). Polymorphisms in the CTLA-4 and CD28 genes, in particular considered together as haplotypes, were associated with increased risk of CCRCC, especially with necrosis and with the advanced stage of disease. The CD28c.-1042G>A SNP modulates the risk of CCRCC in women. These findings indicate that the associations of the CTLA-4 and CD28 polymorphisms with the risk of renal cancer are worth further study in a larger group of patients.
... Our results showed that the presence of T allele of CTLA4 -318 C>T was associated with CRC development which may be related to suppressing the antitumor immune response of T-cells by increasing transcriptional activity, however as a limitation of our study further activation studies will required to improve this hypothesis. In addition, CTLA4 -318 C>T substitution was found to be associated with cervical cancer in that T allele has stronger negative regulation of T-cell proliferation and function (73). However, interestingly, our results show that the frequency of the homozygous CC variant of CTLA4 -318 C>T was higher in patients with CRC than controls, which suggests immunosuppression rather than immunoreactivity due to low levels of CTLA4 as the patients with CRC with CC genotype were found to have a poor prognosis, with higher frequencies of invasion, metastasis or poor differentiation. ...
Background: Colorectal cancer (CRC) is the third most frequent cancer worldwide. Research has revealed the contributions of the immune system and anti-inflammatory pathways in the development of cancer. The balance between cluster of differentiation 28 (CD28) and cytotoxic Tlymphocyte- associated protein 4 (CTLA4) signaling is important for the regulation of immune responses. The oxidant-antioxidant balance by sustaining redox control via several defense mechanisms is also an important factor for the progression of cancer. The aim of the present study was to determine the distribution of CTLA4/CD28 variants and oxidant-antioxidant status in patients with CRC. Materials and Methods: This study enrolled 80 patients with CRC and 115 healthy controls. We used a spectrophotometric assay to detect the levels of lipid peroxidation products malon dialdehyde (MDA) and lipid hydroperoxide (LHP), and measured the concentration of protein damage products, advanced oxidation protein products (AOPP) and protein carbonyl (PCO). Additionally, antioxidant levels were detected by measuring copper, zinc, superoxide dismutase (Zn-Cu SOD) and total thiol (T-SH) levels, and advanced glycation end-products (AGEs). The CTLA4 -318C>T, CTLA4 49A>G and CD28C>T genotypes were determined by using restriction enzymes. Results: AOPP and PCO levels were increased in patients with CRC as well as those of LHP, MDA and AGE, while the levels of antioxidants such as Cu-Zn SOD and T-SH were lower. Lower serum levels of CTLA4 and higher serum levels of CD28 were detected in patients and, an association of the CTLA4 -318C/T polymorphism was found in patients with CRC. Conclusion: Our oxidative stress was increased in patients with CRC, suggesting the contribution of this disturbed oxidative status to serum CTLA4 and CD28 levels, and to the pathogenesis of CRC.
In our previous studies, we found that the rs231775 polymorphism of cytotoxic T-lymphocyte antigen 4 (CTLA-4) is associated with risks of different cancer types; however, the association remains controversial and ambiguous, so we conducted an in-depth meta-analysis to verify the association. A complete search of the PubMed, Google Scholar, Embase, Chinese databases, and Web of Science was conducted without regard to language limitations, covering all publications since November 20, 2021. The search criteria for cancer susceptibility associated with the polymorphism in the CTLA-4 gene rs231775 resulted in 87 case-control studies with 29,464 cases and 35,858 controls. The association strength was analyzed using odds ratios and 95% confidence intervals. Overall, we found that the CTLA-4 rs231775 polymorphism may reduce cancer risk. A stratified cancer type analysis showed that CTLA-4 rs231775 polymorphism was a risk factor for colorectal cancer and thyroid cancer; on the other hand, it was a protective factor for breast cancer, liver cancer, cervical cancer, bone cancer, head and neck, and pancreatic cancer. We also classified cancer into five systems and observed an increased association with digestive tract cancer, decreased associations with orthopedic tumors, tumors of the urinary system, and gynecological tumors. In the subgroup based on race, decreased relationships were observed in both Asians and Caucasians. The same decreased association was also shown in the analysis of the source of control analysis. Our present study indicates that the CTLA-4 rs231775 polymorphism contributes to cancer development and aggression.
Aim
The objective of this study was to discuss the effect of CD152 polymorphisms rs231775, rs3087243 and rs5742909 on the susceptibility to cervical cancer.
Methods
The databases of PubMed, EMBASE, Cochrane Library, ISI Web of Science, Google Scholar Web, CNKI and Wanfang were searched for eligible studies. Chi-square-based Q test examined heterogeneity between included studies, and when Pheterogeneity was less than 0.05, random-effect model was used to calculate odds ratios (ORs) with their 95% confidence intervals (95% CIs); or else, fixed-effect model was selected. Sensitivity analysis was implemented to determine the stability of final results through removing enrolled studies one at a time and then re-obtaining overall estimates. Publication bias among included studies was checked employing Begg’s funnel plot and Egger’s test.
Results
CD152 polymorphism rs231775 decreased cervical cancer risk in total analysis under the genetic models of GG vs. AA, GG vs. AA + AG and G vs. A (OR = 0.73, 95% CI = 0.59-0.91; OR = 0.78, 95% CI = 0.65-0.94; OR = 0.92, 95% CI = 0.87-0.98), and so did the polymorphism rs3087243 in total analysis under the comparisons of AA vs. GG, AA + GA vs. GG, AA vs. GG + GA, A vs. G and GA vs. GG (OR = 0.51, 95% CI = 0.42-0.60; OR = 0.71, 95% CI = 0.62-0.82; OR = 0.57, 95% CI = 0.50-0.66; OR = 0.70, 95% CI = 0.64-0.77; OR = 0.83, 95% CI = 0.72-0.97). Besides, the polymorphism rs5742909 elevated the disease onset in total analysis under the contrasts of TT vs. CC, TT + CT vs. CC, TT vs. CC + CT, T vs. C and CT vs. CC (OR = 2.66, 95% CI = 1.75-4.04; OR = 1.54, 95% CI = 1.24-1.91; OR = 2.13, 95% CI = 1.12-4.03; OR = 1.44, 95% CI = 1.17-1.78; OR = 1.49, 95% CI = 1.22-1.83).
Conclusion
CD152 polymorphisms rs231775 and rs3087243 significantly decrease the risk of cervical cancer, while rs5742909 may increase the disease risk.
Background:
Associations between cytotoxic T lymphocyte antigen-4 (CTLA-4) +49A/G polymorphism and cancer risk are inconclusive. We performed this meta-analysis to derive a more precise estimation of the relationship.
Methods:
A comprehensive literature search was performed using electronic databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.
Results:
A total of 16,358 cases and 19,737 controls from 46 studies were included. Overall, significant association between CTLA-4 +49A/G polymorphism and cancer risk was observed in all genetic models (G vs. A: OR=0.88, 95%CI=0.83-0.93, PH=0.000; GA vs. AA: OR=0.87, 95%CI=0.79-0.97, PH=0.000; GG vs. AA: OR=0.75, 95%CI= 0.65-0.86, PH=0.000; GG vs. GA+AA: OR=0.84, 95%CI=0.79-0.91, PH=0.001; GG+GA vs. AA: OR=0.83, 95%CI=0.74-0.92, PH=0.000). Stratified analysis by cancer type revealed that the CTLA-4+49A/G polymorphism is associated with the decreased risk of cervical cancer, breast cancer, lung cancer, HCC. Further subgroup analysis by ethnicity indicated that there was a statistically decreased cancer risk in Asian population.
Conclusion:
This meta-analysis suggests that CTLA-4+49A/G polymorphism is associated with cancer risk, especially in Asian population.
Cytotoxic T-lymphocyte antigen-4 (CTLA4, CD152) is one of the most fundamental immunosuppressive cytokines that inhibits T-cell activation and terminates the T-cell response by blocking signals stimulated via CD28. A number of studies have assessed the association between CTLA-4 +6230G/A polymorphism and cancer risk. However, the results remain controversial.
In the present study, we performed a meta-analysis to derive a more precise estimation of the relationship. A comprehensive literature search was performed using the PubMed database for relevant articles published (updated to November 21, 2013). Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of the association.
A total of 13 articles with 14 studies were selected for this meta-analysis, including 4,489 cases and 4,715 controls. Combined analysis revealed no associations between CTLA-4 +6230G/A polymorphism and cancer risk. However, in stratified analysis by cancer type, we found that CTLA-4 +6230G/A polymorphism was associated with the risk of breast cancer (AA vs. AG + GG: OR = 0.77, 95 % CI 0.60-0.97, P = 0.03; AA vs. GG: OR = 0.66, 95 % CI 0.46-0.95, P = 0.02) and cervical cancer (AA vs. AG + GG: OR = 0.56, 95 % CI 0.42-0.75, P < 0.01). Additionally, in subgroup analysis based on ethnicity, significant association was also found between the CTLA-4 +6230G/A polymorphism and cancer risk in the Asian population (AA vs. AG + GG: OR = 0.71, 95 % CI 0.59-0.84, P < 0.01).
This meta-analysis indicates that CTLA-4 +6230G/A polymorphism may be associated with a decreased risk of breast cancer and cervical cancer in Chinese population.
Spleen tyrosine kinase (SYK) is a non-receptor type cytoplasmic protein and a known tumor suppressor gene in breast cancer. Polymorphisms in SYK have been reported to be associated with cell invasion/cell morality and an increased risk of cancer development. In this case control study, all exons of the SYK gene and its exon/ intron boundaries were amplified in 200 breast cancer cases and 100 matched controls and then analyzed by single stranded conformational polymorphism. Amplified products showing altered mobility patterns were sequenced and analyzed. Twelve variations were identified in exonic and intronic regions of DNA encoding SH2 domain and kinase domain of the SYK gene. All of these mutations are novel. Among them, 5 missense mutations were observed in exon 15 while one missense mutation was found in exon 8. In addition to these mutations, six mutations were also identified in intronic regions. We found a significant association between SYK mutations and breast cancer and observed that Glu241Arg, a missense mutation is associated with an increase risk of ~7 fold (OR=6.7, 95% CI=1.54-28.8), Thr581Pro (missense mutation) is associated with increased risk of ~16 fold (OR=15.5, 95%CI=2.07-115.45) and 63367 T>G (missense mutation) is associated with increased risk of ~13 fold (OR=12.8, 95%CI=1.71-96.71) for breast cancer. Significant associations were observed for each of these variations with both late menopause (p<0.01) and early menarche (p<0.005) cases when compared to controls. Our findings suggest that the polymorphic gene SYK may contribute to the development of breast cancer in at least the Pakistani population. This study provides an insight view of SYK which may provide a significant finding for the pharmaceutical and biotechnology industry.
BACKGROUND
Several studies have examined associations between genetic variants and the risk of gestational diabetes mellitus (GDM). However, inferences from these studies were often hindered by limited statistical power and conflicting results. We aimed to systematically review and quantitatively summarize the association of commonly studied single nucleotide polymorphisms (SNPs) with GDM risk and to identify important gaps that remain for consideration in future studies.METHODS
Genetic association studies of GDM published through 1 October 2012 were searched using the HuGE Navigator and PubMed databases. A SNP was included if the SNP-GDM associations were assessed in three or more independent studies. Two reviewers independently evaluated the eligibility for inclusion and extracted the data. The allele-specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using random effects models accounting for heterogeneity.RESULTSOverall, 29 eligible articles capturing associations of 12 SNPs from 10 genes were included for the systematic review. The minor alleles of rs7903146 (TCF7L2), rs12255372 (TCF7L2), rs1799884 (-30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) were significantly associated with a higher risk of GDM. Among them, genetic variants in TCF7L2 showed the strongest association with GDM risk, with ORs (95% CIs) of 1.44 (1.29-1.60, P < 0.001) per T allele of rs7903146 and 1.46 (1.15-1.84, P = 0.002) per T allele of rs12255372.CONCLUSIONS
In this systematic review, we found significant associations of GDM risk with nine SNPs in seven genes, most of which have been related to the regulation of insulin secretion.
We investigated the relationship between transforming growth factor-β (TGF-β)-secreting T-regulatory (Tr) cells and anti-B16 melanoma immunity, and studied the association of early cytokines expressed at tumour sites with the generation of Tr cells. A large number of CD4+ Tr cells producing interleukin (IL)-4, IL-10 and TGF-β accumulated with functionally depressed CD8+ cytotoxic T lymphocytes (CTLs) at tumour sites on day 20 after subcutaneous (s.c.) inoculation of B16 tumour cells. Tr cells consisted of two populations, which were termed T helper 3 (Th3) and Tr1 cells. B16-infiltrating Tr cells strongly inhibited the generation of B16-specific T helper 1 (Th1) cells in a TGF-β-dependent manner and were assumed to suppress effective generation of CTLs. In addition, B16 cells markedly progressed in mice transferred adoptively by the cultured B16-infiltrating Tr cells compared with untreated mice. The capacity of these Tr cells to produce TGF-β was hampered by neutralizing anti-IL-10 and partly anti-IL-4 monoclonal antibodies (mAbs) injected intralesionally during the early development of B16 tumours, and this treatment markedly attenuated B16 growth. Furthermore, a lesional injection of recombinant mouse IL-10 at an early tumour site resulted in the vigorous progression of B16 tumours. These results provide evidence that Tr cells, belonging to the T helper 3/T-regulatory 1 (Th3/Tr1) type, are activated in B16-bearing hosts under the influence of T helper 2 (Th2) cytokines, mainly IL-10 (produced at early tumour lesions), and that this regulatory T-cell population functions as a suppressor of anti-B16 immunity.
The T cell protein cytotoxic T lymphocyte antigen 4 (CTLA4) was identified as a crucial negative regulator of the immune system over 15 years ago, but its mechanisms of action are still under debate. It has long been suggested that CTLA4 transmits an inhibitory signal to the cells that express it. However, not all the available data fit with a cell-intrinsic function for CTLA4, and other studies have suggested that CTLA4 functions in a T cell-extrinsic manner. Here, we discuss the data for and against the T cell-intrinsic and -extrinsic functions of CTLA4.
Gene association studies are less appealing in cancer compared to autoimmune diseases. Complexity, heterogeneity, variation in histological types, age at onset, short survival, and acute versus chronic conditions are cancer related factors which are different from an organ specific autoimmune disease, such as Grave's disease, on which a large body of multicentre data is accumulated. For years the focus of attention was on diversity and polymorphism of major histocompatibility complex in respect to human diseases specially the autoimmune diseases, but in recent years, access to other human gene sequences prompted investigators to focus on genes encoding the immune regulatory proteins such as the co-stimulatory, adhesion molecules, cytokines and chemokines and their receptors. Among them, CTLA4 (CD152) has been in the centre of attention for its pivotal role in autoimmunity and cancer. Although not fully understood, CTLA4 with no doubt plays an important role in the maintenance of the immune response by its expression on activated and regulatory T cells. CTLA4 (Gene ID:1493, MIM number:123890) has many variants and polymorphic forms, some present in regulatory positions, some in 3' UTR and the most important one in the leader sequence (+49 A/G). As a pivotal regulatory element of the immune responses magnitude, CTLA4 could be considered as a two-blade knife, for which only the optimal expression ensures an effective, but at the same time, safe immune response. It can accordingly be speculated that CTLA4 alleles associated with extraordinary expression could make a person more susceptible to tumor growth and/or progression. On the other hand, alleles associated with a compromised CTLA4 expression/function may accelerate the formation and/or manifestation of inflammatory autoimmune disorder. I hypothesized a spectrum of the functional dichotomy of CTLA4 SNPs diverging from autoimmunity to cancer. To examine these hypotheses, results from previously published investigations on CTLA4 polymorphisms together with the work done by our own group are discussed in details. Because the most published data are about the polymorphism at position +49, I concentrated on this position; however the data regarding other SNPs are also included for comparison. To support the significance of CTLA4 gene variation in these two major human diseases evidences from organ transplantation are also included. As will be discussed in the manuscript, our work and reports by others from a normal population perspective support the hypothesis that individuals inheriting a GG genotype at position +49, for which lower CTLA4 expression has been extensively suggested, are more susceptible for developing autoimmune disorders and those with AA genotype, with an existence of a state of self-tolerance, may have a higher chance of developing cancer. CTLA4 SNPs may accordingly be considered as a crucial element, along with other known or yet unknown mechanisms, in keeping the immune balance in predisposed individuals to cancer and autoimmunity. Although an spectrum line can be drawn between autoimmunity and cancer by considering published data regarding CTLA4 +49 polymorphism, the extreme functional dichotomy of this SNP appears to be more complex and difficult to understand, but there is no doubt that the future investigations will resolve most ambiguities.
Several variants of CTLA-4 have been reported to be associated with susceptibility systemic lupus erythematosus (SLE); however, findings have been inconsistent across different populations. Using a case-control study design, we have investigated the role of CTLA-4 polymorphism at positions -1661 and -1722 on SLE susceptibility in our Chinese SLE population in central China's Hubei province. Samples were collected from 148 SLE patients and 170 healthy controls. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotypes of the two sites. Statistically significant difference was observed in genotypes for -1722, but not for -1661. The frequency of the T allele on the -1722 SNP was significantly increased in SLE patients: 57.8% versus 40.6% in controls (P < 0.001, OR = 2.002). While the detected C allele frequency in the controls was significantly elevated in comparison to that in the SLE patients (59.4% versus 42.2%). On the contrary, no association was found between SLE and CTLA-4 polymorphism at position -1661.
Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60) (rs3087243), CTLA-4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T>C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA-4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA-4c.49A>G[A] allele and CTLA-4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles CTLA-4c.49A>G[A]/CT60[G]/CD28c.17+3T>C[T]/ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold (p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C>T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.
To investigate the distribution of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) (+49 A/G) gene variants and the association of these variants with the clinical and laboratory findings in Egyptian children with Type-1 Diabetes (T1D).
A case control study was done for 104 Egyptian children with T1D and 78 age and sex matched healthy control. CTLA-4 (+49 A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism (RFLP) method.
CTLA-4 G allele and GG homozygous genotype were significantly increased in T1D patients than in control group (P = 0.047, P = 0.048 respectively). There is no statistical difference between patient with optimal diabetic control (HbA1c < 8.5) and poor control (HbA1c ≥ 8.5) as regarding the CTLA-4 gene variant. The CTLA-4 GG genotype was statistically associated with younger age of patients (P = 0.027) and younger age of presentation (P = 0.036). Insignificant association was found between CTLA-4 alleles / genotypes and diabetic complications.
The CTLA-4 +49 GG homozygous genotype is associated with T1D in Egyptian children especially with younger age of onset and in younger patients, and not associated with grades of diabetic control or diabetic complication.
The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population.
Electronic supplementary material
The online version of this article (doi:10.1007/s00262-009-0751-2) contains supplementary material, which is available to authorized users.
Many studies have shown the central importance of the co-receptors CD28, inducible costimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen 4 (CTLA4) in the regulation of many aspects of T-cell function. CD28 and ICOS have both overlapping and distinct functions in the positive regulation of T-cell responses, whereas CTLA4 negatively regulates the response. The signalling pathways that underlie the function of each of the co-receptors indicate their shared and unique properties and provide compelling hints of functions that are as yet uncovered. Here, we outline the shared and distinct signalling events that are associated with each of the co-receptors and provide unifying concepts that are related to signalling functions of these co-receptors.
Polymorphisms in the TNF-alpha promoter region have recently been shown to be associated with susceptibility to cervical cancer. Some polymorphisms have been reported to influence transcription for this cytokine. Altered local levels in the cervix may influence an individual's immune response, thereby affecting persistence of human papillomavirus (HPV) 16 infection, a primary etiological factor for cervical cancer.
The association of 11 TNF-alpha single-nucleotide polymorphisms (SNPs) with susceptibility to HPV16-associated cervical cancer was investigated. Sequencing of the TNF-alpha promoter region confirmed 10 SNPs, and 1 previously unreported SNP (161 bp upstream of the transcriptional start site) was discovered. Microsphere-array flow cytometry-based genotyping was performed on 787 samples from Hispanic and non-Hispanic white women (241 from randomly selected control subjects, 205 from HPV16-positive control subjects, and 341 from HPV16-positive subjects with cervical cancer). The genotype distribution of 3 SNPs (-572, -857, and -863) was significantly different between case subjects and control subjects. Analysis of haplotypes, which were computationally inferred from genotype data, also revealed statistically significant differences in haplotype distribution between case subjects and control subjects.
We report new associations between several TNF-alpha SNPs and susceptibility to cervical cancer that support the involvement of the TNF- alpha promoter region in development of cervical cancer.
Emerging insights into the mechanisms of activation and negative regulation of innate and adaptive immune cells are providing new opportunities for the development of safe and effective cancer vaccines.
Human papillomavirus (HPV) is considered to be a necessary but not sufficient cause for cervical cancer. The host immunogenetic background plays an important role in the persistence of HPV infection and subsequent development of cervical cancer. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a molecule expressed mainly on activated T cells and is important in the down-regulation of T-cell activation. The aim of this study was to determine if polymorphisms of the CTLA-4 gene are associated with HPV-induced cervical cancer in Taiwanese women. Polymerase chain reaction-restriction fragment length polymorphism was used to genotype -318 C/T, +49 A/G and CT60 A/G polymorphisms in 144 women with cervical squamous cell carcinoma (CSCC) and 378 ethnicity-matched healthy control women. The presence and genotypes of HPV in CSCC were determined by E6-, E7-based nested polymerase chain reaction. The frequency of C/T genotype of -318 C/T polymorphism was significantly higher in patients with HPV-16-positive CSCC compared with controls (odds ratio = 1.99, 95% confidence interval = 1.16-3.42, P(c) = 0.03). No significant associations were found for +49 A/G and CT60 A/G polymorphisms. Analysis of haplotypes, computationally inferred from genotype data, also revealed no significant differences in distribution among all subjects with CSCC, those with HPV-16-positive CSCC and controls. Our results suggest that the -318 C/T variant in the promoter region of the CTLA-4 gene is associated with HPV-16-associated CSCC in Taiwanese women.
The host immunogenetic background plays an important role in the development of breast cancer. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a molecule expressed predominantly on activated T cells and is important during the down-regulation of T-cell activation. To evaluate the potential influences of CTLA-4 gene polymorphisms on breast cancer risk, a case-control study was conducted in Han women of Northeast China.
We genotyped CTLA-4 variants (-1661 G/A, -658 T/C, -318 T/C, +49 G/A and CT60 G/A) to tag all common haplotypes (>or= 1% frequency) in 117 Chinese breast cancer cases and 148 age/sex matched healthy individuals. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Data was analyzed using the Chi-square test and Haploview software.
The frequency of CTLA-4 -1661G allele, -318T allele and CT60G allele carriers was significantly higher in patients than in controls (P = 0.0057, OR 1.91, 95% CI 1.21-3.02; P = 0.0031, OR 2.39, 95% CI 1.34-4.27; P = 0.023, OR 1.52, 95% CI 1.06-2.17, respectively). The -658T allele carrier frequency was significantly lower than in controls (P = 0.0000082, OR 0.17, 95% CI 0.08-0.37), whereas the +49A allele was significantly associated with tumor size in patients (P = 0.0033). Two common CTLA-4 haplotypes, ATCGA and ATCAG, were higher in healthy controls than patients (P = 0.0026, OR 0.17, 95% CI 0.05-0.54; P = 0.034, OR 0.12, 95% CI 0.02-0.92, respectively). A strong association was observed between tumor size and the ACCAA, ACCAG and ACCGA haplotypes (P = 0.0032, P = 0.0000031 and P = 0.017).
These results suggest that polymorphisms of the CTLA-4 gene may modify individual susceptibility to and progression of breast cancer in Chinese Han women.
The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer.
Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) plays a key role in restraining the adaptive immune response of T-cells towards a variety of antigens including tumor associated antigens (TAA). The blockade of this immune checkpoint elicits an effective anticancer immune response in a range of preclinical models, suggesting that naturally occurring (or therapeutically induced) TAA specific lymphocytes need to be "unleashed" in order to properly fight against malignant cells. Therefore, investigators have tested this therapeutic hypothesis also in humans: the favorable results obtained with this strategy in patients with advanced cutaneous melanoma are revolutionizing the management of this highly aggressive disease and are fueling new enthusiasm on cancer immunotherapy in general. Here we summarize the biology of CTLA-4, overview the experimental data supporting the rational for targeting CTLA-4 to treat cancer and review the main clinical findings on this novel anticancer approach. Moreover, we critically discuss the current challenges and potential developments of this promising field of cancer immunotherapy.
Despite decades of research, current cancer therapies extend survival but often do not actually cure the disease. Immune cell based therapy is described here that can eliminate tumor cells without the toxicity associated with chemotherapy or allogeneic bone marrow transplant (BMT). Allogeneic BMT has beneficial graft vs. tumor (GVT) effects but accompanied by the undesirable graft vs. host disease (GVHD). The mechanism described here relates to generating the Mirror EffectTM that elicits a host vs. tumor (HVT) effect along with a non-toxic host vs. graft (HVG) response. The HVT effect generated by inducing the Mirror EffectTM in a host is effective in cancer therapy, as well as other diseases. The patent strategy, employed for successful patent prosecution related to the elucidation of the Mirror EffectTM, is also discussed.
Human papillomavirus (HPV) is the most important etiological factor for cervical cancer. A recent study demonstrated that more than 20 HPV types were thought to be oncogenic for uterine cervical cancer. Notably, more than one-half of women show cervical HPV infections soon after their sexual debut, and about 90 % of such infections are cleared within 3 years. Immunity against HPV might be important for elimination of the virus. The innate immune responses involving macrophages, natural killer cells, and natural killer T cells may play a role in the first line of defense against HPV infection. In the second line of defense, adaptive immunity via cytotoxic T lymphocytes (CTLs) targeting HPV16 E2 and E6 proteins appears to eliminate cells infected with HPV16. However, HPV can evade host immune responses. First, HPV does not kill host cells during viral replication and therefore neither presents viral antigen nor induces inflammation. HPV16 E6 and E7 proteins downregulate the expression of type-1 interferons (IFNs) in host cells. The lack of co-stimulatory signals by inflammatory cytokines including IFNs during antigen recognition may induce immune tolerance rather than the appropriate responses. Moreover, HPV16 E5 protein downregulates the expression of HLA-class 1, and it facilitates evasion of CTL attack. These mechanisms of immune evasion may eventually support the establishment of persistent HPV infection, leading to the induction of cervical cancer. Considering such immunological events, prophylactic HPV16 and 18 vaccine appears to be the best way to prevent cervical cancer in women who are immunized in adolescence.
Cervical cancer is the commonest cancer cause of death among women in developing countries and efforts to prevent the disease using newer approaches and HPV vaccination need to be explored. Detection of cervical cancer at an early stage is associated with excellent survival but most women in developing countries present with advanced and often untreatable disease, with very poor survival. The ratio between incidence and mortality from cervical cancer remains very high, largely due to lack of access to appropriate anti-cancer therapies in developing countries. In developed countries with functional screening programs, cervical cancer has been rendered a relatively rare disease. Ongoing efforts to refine the characteristics of screening tests continue, as does implementation of current HPV vaccines for the primary prevention of cervical cancer.
Several single nucleotide polymorphisms (SNPs) have been associated with susceptibility to autoimmune diseases, but the mechanisms responsible for the associations are poorly understood. To test the hypothesis that the variation of the basal levels of the gene products is significantly influenced by genetic polymorphism, we investigated whether SNPs in genes CD40, CD28, CTLA4, CD80, CD86, BAFF and IL6 are affecting mRNA or protein expression. The surface expression of the proteins on unstimulated monocytes, B cells, NK cells, CD4+ T cells and CD8+ T cells, as well as the mRNA levels in peripheral blood mononuclear cells (PBMC) was compared among healthy volunteers with different genotypes. Despite the low basal expression level and large interindividual variation, average BAFF expression was significantly higher in carriers of genotype C/C of the BAFF-871C>T SNP (rs9514828) when compared with carriers of the C/T and T/T genotypes. Genotype C/C carriers presented higher levels of the protein on CD8+ T cells, monocytes and NK cells and of mRNA in PBMC. Moreover, carriers of T allele of CTLA4-318C>T (rs5742909) showed a significantly increased expression of CTLA-4 on CD8+ T cells. No significant variation among genotypes was found in the protein or mRNA levels of other investigated genes.
To explore the regulatory mechanism of Xiaoyin Recipe () on the T helper 1/T helper 2 (Th1/Th2) immune balance.
Thirty-six experimental animals were divided into three groups, 12 rats in each group: blank control group (B group), negative control group (N group), and Xiaoyin Recipe treatment group (T group). The latter two groups received immunization of experimental autoimmune thyroiditis (EAT), and T group were treated with Xiaoyin Recipe for a month. Then, the expression of Th1-Th2-related genes in peripheral blood mononuclear cells (PBMCs) were screened with Oligo GEArray Rat Th1-Th2-Th3 Microarray. The expressions of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), T-box expressed in T-cells (T-bet), and GATA-binding protein-3 (GATA-3) were detected by real-time polymerase chain reaction (RT-PCR).
Gene array screening showed that compared to N group, in T group after Xiaoyin Recipe treatment, 3 genes were upregulated in EAT rats, including interleukin-27 receptor alpha (IL-27rα), glomulin (Glmn), and GATA-3, while 38 genes were downregulated, such as CD28, IL-18, signal transducer, and activator of transcription 1 (STAT1), T-bet, TNF receptor superfamily member 4 (TNFRSF4), TNF ligand superfamily member 5 (TNFSF5), and TNF receptor superfamily member 5 (TNFRSF5). While RT-PCR showed that there was an increased level of TNF-α mRNA (P<0.01), an elevated ratio of T-bet/GATA-3, and a decreased level of IL-10 mRNA in PBMC of N and T group compared to B group (P <0.01); and after treatment with Xiaoyin Recipe, IL-10 mRNA level increased (P <0.01), while TNF-α mRNA level and T-bet/GATA-3 ratio decreased in T group compared to N group (P <0.01).
Xiaoyin Recipe for psoriasis could induce a Th1/Th2 balance drift toward Th2 in PBMC of EAT rats and thus improve the conditions.
This study was to investigate whether the common polymorphisms of CD40 and CTLA4 genes confer susceptibility to AITD in the Chinese population. A set of unrelated subjects including 303 GD patients, 208 HT patients, and 215 matched healthy controls were recruited. SNPs were genotyped by the method of PCR-RFLP. (1) As for CD40 C/T(-1) SNP, only a significant difference was found in allele frequencies between GD and control groups (P = 0.033). (2) On the part of CTLA-4 A/G(49) SNP, significant differences were found in genotype and allele frequencies between GD and control groups (P = 7.0 × 10(-5) and P = 0.002, respectively), and similar results were found between HT and control groups (P = 0.015 and P = 0.003, respectively). (3) The logistic regression analysis showed there was no interaction between CD40 and CTLA4 genotypes (P = 0.262). These results indicate that both CTLA-4 A/G(49) and CD40 C/T(-1) SNPs are associated with genetic susceptibility of GD, and CTLA-4 A/G(49) is also associated with HT.
To study the effect of cytotoxic T-lymphocyte antigen 4 gene haplotypes to susceptibility of esophageal squamous cell carcinoma.
A gender- and age-matched case-control design was used in this study. PCR-RFLP method was used to detect the genotype of CTLA4 in 205 patients and 205 control individuals in the Anyang area. Furthermore, haplotypes were calculated by PHASE2.1 software. Finally, the conditional logistic regression analysis was carried out to analyze the relevance between the risk of ESCC and the genotypes or haplotypes of CTLA4 gene.
The CTLA4 rs231775 and rs4553808 genotypes in patients with ESCC were significantly different from controls (p=0.004, p=0.023, respectively). The AG and AA genotypes of rs231775 were highly correlated with the risk of ESCC (Adjusted OR=2.280, 95%CI=1.433-3.629, p=0.001; Adjusted OR=2.192, 95%CI=1.229-3.911, p=0.008, respectively), and AG genotype of rs4553808 also increased the susceptibility of ESCC (Adjusted OR=1.848, 95%CI=1.220-2.800, p=0.004). Further study suggested that AAG haplotype may enhance the risk of ESCC (Adjusted OR=5.035, 95%CI=1.599-15.860, p=0.005), but GAA haplotype played a protective role (Adjusted OR=0.413, 95%CI=0.251-0.680, p=0.001).
Our research confirmed that CTLA4 genetic variation was related to ESCC in the Anyang area and GAA haplotype was the protective factor of ESCC.
Despite the knowledge of many genetic alterations present in osteosarcoma, the complexity of this disease precludes placing its biology into a simple conceptual framework. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays important roles in downregulating T-cell activation, thereby attenuating anti-tumor responses and increasing cancer susceptibility. Polymorphisms in the CTLA-4 gene are associated with different autoimmune diseases and cancers. The current study evaluated the association of four CTLA-4 gene mutations, -1661A/G (rs4553808), -318C/T (rs5742909), +49G/A (rs231775), and CT60A/G (rs3087243), with osteosarcoma in the Chinese population. CTLA-4 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in 267 osteosarcoma patients and 282 age-matched healthy controls. Results showed that the CTLA-4 gene +49 AA genotype, +49 A allele, and GTAG haplotype were significantly more frequent in osteosarcoma patients than in controls (odds ratio [OR] 2.20, 95% confidence interval [CI] 1.23-2.95, p = 0.007; OR 1.32, 95% CI 1.03-1.69, p = 0.029, and OR = 1.47, 95% CI 1.03-2.09, p = 0.033, respectively). The CTLA-4 +49G/A polymorphism and GTAG haplotype are associated with increased risk of osteosarcoma.
The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia.
One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
During the past 20 years, several types of human papillomaviruses (HPVs) have been identified that cause specific types of cancers. The etiology of cancer of the cervix has been linked to several types of HPV, with a high preponderance of HPV16. The role of these virus infections has been established 1) by the regular presence of HPV DNA in the respective tumor biopsy specimens, 2) by the demonstration of viral oncogene expression (E6 and E7) in tumor material, 3) by the identification of transforming properties of these genes, 4) by the requirement for E6 and E7 expression for maintaining the malignant phenotype of cervical carcinoma cell lines, 5) by the interaction of viral oncoproteins with growth-regulating host-cell proteins, and 6) by epidemiologic studies pointing to these HPV infections as the major risk factor for cervical cancer development. In addition to cancer of the cervix, a major proportion of anal, perianal, vulvar, and penile cancers appears to be linked to the same HPV infections. In addition, close to 20% of oropharyngeal cancers contain DNA from the same types of HPV. Recent evidence also points to a possible role of other HPV infections in squamous cell carcinomas of the skin. This review covers recent developments in understanding molecular mechanisms of HPV carcinogenesis, mainly discussing functions of viral oncoproteins and the regulation of viral oncogenes by host-cell factors. Modifications in host-cell genes, most likely engaged in the control of HPV gene expression in proliferating cells, emerge as important events in HPV-mediated carcinogenesis.
Activation of T cells requires at least two signals transduced by the Ag-specific TCR and a costimulatory ligand such as CD28. CTLA-4, expressed on activated T cells, binds to B7 present on APCs and functions as a negative regulator of T cell activation. Our laboratory previously reported the association of Graves' disease (GD) with a specific CTLA-4 gene polymorphism. In theory, reduced expression or function of CTLA-4 might augment autoimmunity. In the present study, we categorized autoimmune thyroid disease patients and normal controls (NC) by genotyping a CTLA-4 exon 1 polymorphism and investigated the function of CTLA-4 in all subjects. PBMCs and DNA were prepared from GD (n = 45), Hashimoto's thyroiditis (HT) (n = 18), and NC (n = 43). There were more GD patients with the G/G or A/G alleles (82.2% vs 65.1% in NC), and significantly fewer patients with the A/A allele (17.8% vs 34.9% in NC). In the presence of soluble blocking anti-human CTLA-4 mAb, T cell proliferation following incubation with allogeneic EBV-transformed B cells was augmented in a dose-dependent manner. Augmentation induced by CTLA-4 mAb was similar in GD and NC (GD, HT, NC = 156%, 164%, 175%, respectively). We related CTLA-4 polymorphism to mAb augmentation of T cell proliferation in each subgroup (GD, HT, NC). Although PBMC from individuals with the G/G alleles showed 132% augmentation, those with the A/A alleles showed 193% augmentation (p = 0.019). CTLA-4 polymorphism affects the inhibitory function of CTLA-4. The G allele is associated with reduced control of T cell proliferation and thus contributes to the pathogenesis of GD and presumably of other autoimmune diseases.
The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an important modifier of T-cell activation with down-regulatory properties upon B7 engagement. An allelic polymorphism in exon 1 of the CTLA4 gene coding for the peptide leader sequence of CTLA4 was recently described. This polymorphism was detected in association with several autoimmune diseases. In this study, we investigated the functional impact of the CTLA4 exon 1 +49 A/G dimorphism on T-cell activation and cellular localization. We examined the T-cell response from healthy donors either homozygous for A or G at position +49 of the exon 1. Under suboptimal stimulation conditions we found a greater proliferative response of cells from donors homozygous for G at position +49. FACS analysis of CTLA4 expression revealed a reduced up-regulation of CTLA4 from G/G donors upon T-cell activation, if compared with wild-type cells. Intracellular CTLA4 distribution demonstrated qualitatively different staining patterns between the two genotypes as determined using confocal fluorescence microscopy. Our results suggest that the G allele at position +49 of exon 1 affects the CTLA4-driven down-regulation of T-cell activation and may be an important factor in the pathogenesis of autoimmune diseases.
The discovery of multiple costimulatory cell surface molecules that influence the course of T cell activation has increased our appreciation of the complexity of the T cell response. It remains clear, however, that CD28 and cytotoxic T lymphocyte antigen 4 (CTLA-4) are the critical costimulatory receptors that determine the early outcome of stimulation through the T cell antigen receptor (TCR). Details of how the T cell integrates TCR stimulation with the costimulatory signals of CD28 and the inhibitory signals of CTLA-4 remain to be established, but unique features of the cell biology of CTLA-4 provide important insights into its function. We summarize here recent findings that suggest a previously unrecognized role for CTLA-4 in the regulation of T cell responses. We also describe preclinical and clinical results that indicate manipulation of CTLA-4 has considerable promise as a strategy for the immunotherapy of cancer.
Polymorphism in genes encoding T-cell regulatory proteins and cytokines may influence inflammation and cancer development via regulation of antitumor immune response. In the current study we analyzed genotypic frequencies of cytotoxic T-lymphocyte antigen-4 (CTLA-4)/CT60, CTLA-4/A49G, interleukin (IL)-4, and IL-10 polymorphisms in 117 renal cell carcinoma patients, 96 patients with colorectal cancer, and 196 healthy controls to test for an association between polymorphism in these genes and the risk of renal and colon cancer in a Spanish group of patients. In the case-control study, DNA samples from cancer patients and controls were analyzed using a TaqMan single nucleotide polymorphism genotyping assay. The distribution of IL-4 and IL-10 polymorphisms was similar between renal cancer patients and controls. However, a higher incidence of CTLA-4/CT60-AA genotype (p = 0.005; odds ratio (OR)= 2.12 with 95% confidence interval (CI): 1.28-3.50) and CTLA-4/A49G-AA (p = 0.022; OR = 1.76 with 95% CI: 1.11-2.80) genotype was observed in renal cancer patients than in controls. In addition, we observed a positive correlation between the AA genotype in both CTLA-4 polymorphisms and RCC grade, suggesting a role for the CTLA4 gene in tumor development. Therefore, our data suggest the CTLA-4 gene may be a candidate as a renal adenocarcinoma susceptibility gene, but does not play an important role in colon cancer.
1) and CTLA-4 A/G(49) SNPs are associated with autoimmune thyroid diseases in the Chinese population
- Yang J Q Qin
- Yan N Zhu
- Li C Yf
- Yang
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Yang J, Qin Q, Yan N, Zhu YF, Li C, Yang XJ, et al. CD40 C/T(-1) and CTLA-4 A/G(49) SNPs are associated with autoimmune thyroid diseases in the Chinese population. Endocrine 2012;41(1):111–5.
Enhancement of antitumor immunity by CTLA-4 blockade
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Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271(5256):1734–6.
CTLA-4: new insights into its biological function and use in tumor immunotherapy
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- Allison
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Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002;3(7):611–8.