Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer

Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia 19104, USA.
New England Journal of Medicine (Impact Factor: 55.87). 01/2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177
Source: PubMed


Although tumor-infiltrating T cells have been documented in ovarian carcinoma, a clear association with clinical outcome has not been established.
We performed immunohistochemical analysis of 186 frozen specimens from advanced-stage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction.
CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8 percent); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent among patients whose tumors contained no T cells in islets. Significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons) were also seen among 74 patients with a complete clinical response after debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.9 percent among patients whose tumors contained T cells and 11.9 percent among patients whose tumors contained no T cells in islets. The presence of intratumoral T cells independently correlated with delayed recurrence or delayed death in multivariate analysis and was associated with increased expression of interferon-gamma, interleukin-2, and lymphocyte-attracting chemokines within the tumor. The absence of intratumoral T cells was associated with increased levels of vascular endothelial growth factor.
The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma.

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    • "This failure may partially be attributed to most studies being directed towards the tumour cell-intrinsic events and ignoring the contributory effects of variation in the local immune response. The role of the tumour microenvironment in the survival of tumour cells, and the dual roles of cancer immunoediting via tumour-promoting inflammation and suppression, is becoming well recognised (Zhang et al, 2003; Galon et al, 2006; Schreiber et al, 2011; Baxevanis et al, 2013). There is also increasing awareness that pre-existing adaptive immune status affect response to subsequent therapy across various cancers. "
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    ABSTRACT: Background: Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype. Methods: Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform. Results: A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models. Conclusions: This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.
    British Journal of Cancer 03/2015; DOI:10.1038/bjc.2015.81 · 4.84 Impact Factor
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    • "Cells of the immune system Function Reference CD3+ T lymphocytes The presence of infiltrating lymphocytes is associated with a higher rate Zhang et al., 2003 [25] of survival in patients diagnosed with ovarian cancer Stage III and IV compared with those patients who did not have such lymphocytes; the presence of these lymphocytes is related to a better prognosis of the clinical response ovarian cancer. T CD3+ CD8+ The presence of these lymphocytes is related to a better prognosis for the Helal et al., 2004 [26] lymphocytes clinical response of ovarian cancer. "
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    ABSTRACT: The objective of study was review studies that have investigated the immune response in the presence of a malignant ovarian neoplasia. A review of the literature was performed to identify studies of malignant ovarian neoplasia, particularly studies that addressed the potential for cytokines, nitric oxide, and lymphocytes to mediate an immune response against ovarian cancer. Certain subsets of tumor-infiltrating leukocytes and/or tumor-associated leukocytes have been found to correlate with an improved disease prognosis, while other lymphocyte subsets (such as CD3+/CD4+/CD25+ T cells) have been associated with a poor diagnosis. These data suggest that cytokines can have a protective role, or can promote an immune system defense against a cancer. In particular, certain cytokines (e.g., IL 8, IL 10) represent attractive candidates for the development of new diagnostic, prognostic, and therapeutic strategies for the treatment of ovarian cancer. Keywords: Cytokines, nitric oxide, malignant ovarian neoplasia, cluster of differentiation, lymphocytes.
    European journal of gynaecological oncology 11/2014; 35(5):487-491. · 0.61 Impact Factor
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    • "In breast, colorectal and lung cancer, as well as HCC, the status of the stroma and the local adaptive immune response are superior prognostic factors compared with tumor phenotype or clinical staging (11–14). In clinicopathological practice, intratumoral infiltration of CD4 or CD8 T cells was found to be correlated with lower disease recurrence and improved survival rates in HCC (14–16) and ovarian carcinoma (17). Furthermore, HCC tumor size was also found to have prognostic significance (7,18,19). "
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    ABSTRACT: Tumor-infiltrating lymphocytes may be a manifestation of antitumor immunity. In the present study, hepatocellular carcinoma (HCC) and pericancerous non-tumor liver tissues samples were obtained from 86 surgical patients who had not received preoperative treatment. The cellular expression levels of CD4 and CD8 were immunohistochemically examined in the two tissue groups using tissue microarrays, to evaluate their clinicopathological relevance. Immunohistochemically, CD4 and CD8 T cells were observed in the tumor parenchyma and tumor stroma, and the intensity of CD4 and CD8 immunoreactivity was homogeneous in all HCC samples examined. Morphometrically, the average numbers of CD4- and CD8-positive T cells were significantly increased in the tumor stroma, compared with those in the tumor parenchyma (tumor stroma versus tumor parenchyma: 22±3.6 versus 7.4±0.9 in CD4, 32.8±4.2 versus 16±2.5 in CD8; both P<0.01). Furthermore, the average numbers of CD8-positive T cells in the tumor parenchyma and stroma were significantly increased, compared with the average numbers of CD4-positive cells (P<0.05). In addition, in the tumor parenchyma and stroma, the average numbers of CD8 T cells were significantly higher in patients with tumor diameters ≤5 cm compared with those in patients with tumor diameters >5 cm (diameter ≤5 cm versus diameter >5 cm: 18.1±3.3 versus 12.2±3.8 in tumor parenchyma, 36.5±4.8 versus 21.9±8.9 in tumor stroma; both P<0.05). In addition, CD8 expression was significantly enhanced in patients with chronic hepatitis and cirrhosis, compared with paired tumor parenchymal tissues (P<0.01). Furthermore, a significant positive correlation was observed between CD4 and CD8 expression in the tumor parenchyma and stroma (both P<0.001). These observations suggest that tumor parenchyma- or stroma-infiltrating CD8 T cells may be involved in HCC tumor diameter control.
    Oncology letters 11/2014; 8(5):2284-2290. DOI:10.3892/ol.2014.2516 · 1.55 Impact Factor
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