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Head and neck squamous cell carcinoma (HNSCC) immune landscape and implications for immunotherapy. (A) HNSCC tumors possess the highest median Treg infiltration and the highest Treg/CD8 + T cell infiltration ratio of the 10 most immune-infiltrated tumors, providing a strong rationale to target modulators of Treg function such as CTLA-4, GITR, ICOS, IDO, VEGFA, and others in head and neck cancer immunotherapy. (B) HNSCC tumors possess the highest median CD56 dim NK cell infiltration of the 10 most immune-infiltrated tumors providing, an additional rationale to augment NK cell activity in head and neck cancer via modulation of suppressive and agonistic receptors found on NK cells such as KIR, PD-1, TIGIT, 4-1BB, and others. (C) Patients displaying molecular smoking signatures possessed lower immune infiltration of their tumors and displayed worse survival, suggesting these patients may benefit from immune stimulatory therapy such as IL-2, TLR, and STING agonists. Green arrows indicate stimulatory signals and red arrows indicated inhibitory signals.
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Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will re...
Contexts in source publication
Context 1
... to immune checkpoint inhibition have been found to correlate with mutation count in sev- eral cancer types (25)(26)(27). This has been attributed to the creation of immunogenic peptides resulting from somatic mutations (neoantigens). These result when mutations lead to the generation of immunogenic neoepitopes presented to the immune system via MHC class I molecules. While there was no clear correla- tion across cancer types between levels of immune infiltration and nonsynonymous mutational burden (the total number of nonsilent missense mutations per tumor), both HPV-positive and HPV-negative tumors exhibited moderate-to-high mutation counts, comparable with those of other tumor types that have been found to respond to immune checkpoint blockade: melanoma, lung squamous cell carcinoma, and lung adenocarcinoma. The generally high levels of immune infiltration and mutational burden in HPV-positive and HPV-negative HNSCC together provide a strong rationale for investigation of immunotherapy in these tumors (17,(28)(29)(30)) (Supplemental Figure ...
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... unique aspects of the immune infiltrative landscape of HNSCC are highly relevant to ongo- ing investigation in immuno-oncology ( Figure 6): (a) Smoking-signature-high, HPV-negative HNSCCs have high mutational loads, but low levels of immune infiltration and activation. These tumors have poorer clinical outcome, after adjustment for HPV and other clinical and molecular factors. These immunologically cold but mutation/neoantigen-rich tumors may therefore benefit from immune agonists in combination with immune checkpoint blockade. (b) HPV-positive and HPV-negative HNSCC tumors are among the most highly immune-infiltrated cancer types, and possess the highest degrees of Treg infiltration. These tumors are poised to benefit from immunotherapy that includes Treg-targeted approaches. (c) Both HPV-positive and HPV-negative HNSCC have the highest levels of NK cell infiltration, suggesting that immunotherapeu- tic approaches inhibiting NK cell checkpoints may have unique applicability in head and neck ...
Context 3
... to immune checkpoint inhibition have been found to correlate with mutation count in sev- eral cancer types (25)(26)(27). This has been attributed to the creation of immunogenic peptides resulting from somatic mutations (neoantigens). These result when mutations lead to the generation of immunogenic neoepitopes presented to the immune system via MHC class I molecules. While there was no clear correla- tion across cancer types between levels of immune infiltration and nonsynonymous mutational burden (the total number of nonsilent missense mutations per tumor), both HPV-positive and HPV-negative tumors exhibited moderate-to-high mutation counts, comparable with those of other tumor types that have been found to respond to immune checkpoint blockade: melanoma, lung squamous cell carcinoma, and lung adenocarcinoma. The generally high levels of immune infiltration and mutational burden in HPV-positive and HPV-negative HNSCC together provide a strong rationale for investigation of immunotherapy in these tumors (17,(28)(29)(30)) (Supplemental Figure ...
Context 4
... unique aspects of the immune infiltrative landscape of HNSCC are highly relevant to ongo- ing investigation in immuno-oncology ( Figure 6): (a) Smoking-signature-high, HPV-negative HNSCCs have high mutational loads, but low levels of immune infiltration and activation. These tumors have poorer clinical outcome, after adjustment for HPV and other clinical and molecular factors. These immunologically cold but mutation/neoantigen-rich tumors may therefore benefit from immune agonists in combination with immune checkpoint blockade. (b) HPV-positive and HPV-negative HNSCC tumors are among the most highly immune-infiltrated cancer types, and possess the highest degrees of Treg infiltration. These tumors are poised to benefit from immunotherapy that includes Treg-targeted approaches. (c) Both HPV-positive and HPV-negative HNSCC have the highest levels of NK cell infiltration, suggesting that immunotherapeu- tic approaches inhibiting NK cell checkpoints may have unique applicability in head and neck ...
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Citations
... Unfortunately, patients with head and neck squamous cell carcinoma (HNSCC), particularly specific subtypes thereof, exhibit low response rates to immunotherapy [8,9]. The precise mechanistic basis for this resistance remains enigmatic; nevertheless, it can potentially be ascribed to intricate interactions occurring within the tumor microenvironment (TME), which assumes a crucial role in driving cancer progression [10,11]. Therefore, comprehensive exploration of the immuno-microenvironment is imperative for establishing a theoretical foundation guiding immunotherapeutic strategies against laryngeal squamous cell carcinoma. ...
The infiltration and prognostic significance of tumor-infiltrating plasmacytoid dendritic cells (TI-pDC) have been elucidated in various human solid cancers. However, the infiltrating patterns and functional importance of TI-pDC in laryngeal squamous cell carcinoma (LSCC) remain unknown. In this study, flow cytometric analyses were conducted to characterize the infiltration of dendritic cells and T lymphocytes, along with their respective subgroups in tumor tissues (TT), para-carcinoma tissues (PT), and peripheral blood (PB) from LSCC patients. Immunohistochemical staining for CD4 and CD8, as well as immunofluorescence staining for CD123, were performed on serial tissue sections to investigate the co-localization of TI-pDC and tumor-infiltrating T lymphocytes (TIL) within the tumor microenvironment (TME). Our results demonstrated significantly lower percentages of all three DC subsets in PB compared to TT and PT. Notably, the pDC percentage was markedly higher in TT than in PT. Moreover, TI-pDC percentage was significantly elevated in N⁺ stage patients compared to those with N0 stage. The results of survival analysis consistently demonstrated that high levels of TI-pDC infiltration were indicative of a poor prognosis. Further investigation revealed a significant negative correlation between TI-pDC and CD8⁺ TILs; notably, pDCs expressed an inhibitory surface molecule PD-L2 rather than PD-L1 within PT. Collectively, our findings suggest that increased TI-pDC is associated with adverse outcomes in LSCC patients while exhibiting an inhibitory phenotype that may play a crucial role in suppressing CD8⁺ TILs within LSCC tumors. These results highlight the potential therapeutic strategy targeting PD-L2⁺ pDCs for immunotherapies against LSCC.
... Moreover, the large-scale multi-institutional genomic analyses using The Cancer Genome Atlas (TCGA) data have revealed not only comprehensive landscape of somatic genomic alterations that may underlie ENE, but also patterns of immune infiltration status in head and neck cancer associated with patient clinical outcomes. However, there are no obvious molecular markers of ENE that clearly point to the underlying mechanistic processes that lead to extension of tumor beyond the lymph node capsule [3,[10][11][12][13][14]. The association between immune infiltration status in primary tumors and ENE-positive tumors or patient clinical outcome in the ENE-positive group also have not been described. ...
... ssGSEA score is an allocated score for each immune cell based on RNA expression level of signature genes by comparing the levels of these gene set with all other genes [21]. Analyses of multiple cancer types have previously used this scoring system for profiling the overall immune infiltration [13,20]. The signature gene set, which is preferentially expressed in 24 immune cells, was published by Bindea et al [22]. ...
... Patients with HNSCC are currently stratified by HPV/p16 status and clinical variables; however, there is a large variability in the response to therapy within these groups. Attempts to characterize HNSCC based on immune infiltrate and link these characterizations to outcomes have been hampered by small numbers, the heterogeneity of HNSCC itself, and a lack of uniformly treated patients [29][30][31]. The correlation of the Th2 infiltrate with other pathways, specifically the Cell Cycle Control of Chromosomal Replication Pathway as well as the Kinetochore Metaphase Signaling Pathway was performed across the TCGA, ICGC, and CPTAC cohorts ( Figure A3). ...
... Patients with HNSCC are currently stratified by HPV/p16 status and clinical variables; however, there is a large variability in the response to therapy within these groups. Attempts to characterize HNSCC based on immune infiltrate and link these characterizations to outcomes have been hampered by small numbers, the heterogeneity of HNSCC itself, and a lack of uniformly treated patients [29][30][31]. ...
Simple Summary
Locoregional recurrence following the definitive treatment of head and neck cancers often leads to patient demise. Radiation is frequently used in the definitive treatment of these cancers. Resistance to radiation leads to increased locoregional recurrence, particularly in patients with human papillomavirus-negative head and neck squamous cell carcinomas. In this study, we show that tumor Th2 immune infiltrate is associated with increased locoregional recurrence in patients with human papillomavirus-negative head and neck squamous cell carcinoma. These findings can be used to develop novel immunotherapeutic approaches to improve the response to radiation and thus decrease locoregional recurrence and improve outcomes in patients with human papillomavirus-negative head and neck squamous cell carcinomas.
Abstract
The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene expression. The immune cell types significantly associated with outcomes in the discovery cohort were examined in the independent validation cohort. A positive association between high Th2 infiltration and LRR was identified in the discovery cohort and validated in the validation cohort. Tumor mutations in CREBBP/EP300 and CASP8 were significantly associated with Th2 infiltration. A pathway analysis of genes correlated with Th2 cells revealed the potential repression of the antitumor immune response and the activation of BRCA1-associated DNA damage repair in multiple cohorts. The Th2 infiltrates were enriched in the HPV/p16-negative HNSCC tumors and associated with LRR and mutations in CASP8, CREBBP/EP300, and pathways previously shown to impact the response to radiation.
... The composition and abundance of immune cells in tumours differ significantly between HPV-positive and HPV-negative cases [35,36]. HPV-positive tumours generally exhibit higher levels of tumour-infiltrating lymphocytes (TILs) compared to HPV-negative tumours. ...
The World Health Organisation recognised human papillomavirus (HPV) as the cause of multiple cancers, including head and neck cancers. HPV is a double-stranded DNA virus, and its viral gene expression can be controlled after infection by cellular and viral promoters. In cancer cells, the HPV genome is detected as either integrated into the host genome, episomal (extrachromosomal), or a mixture of integrated and episomal. Viral integration requires the breakage of both viral and host DNA, and the integration rate correlates with the level of DNA damage. Interestingly, patients with HPV-positive head and neck cancers generally have a good prognosis except for a group of patients with fully integrated HPV who show worst clinical outcomes. Those patients present with lowered expression of viral genes and limited infiltration of cytotoxic T cells. An impediment to effective therapy applications in the clinic is the sole testing for HPV positivity without considering the HPV integration status. This review will discuss HPV integration as a potential determinant of response to therapies in head and neck cancers and highlight to the field a novel therapeutic avenue that would reduce the cancer burden and improve patient survival.
... Head and neck squamous cell carcinoma (HNSCC) is estimated to be the sixth most common cancer worldwide [1,2]. The incidence of HNSCC continues to rise and is expected to increase by 30% by 2030 [1][2][3], with mortality rates reported between 40 and 50% [4]. HNSCC is clinically divided into two major divisions: human papillomavirus (HPV) related (HPV+) and unrelated (HPV−). ...
Clinically approved head and neck squamous cell carcinoma (HNSCC) immunotherapies manipulate the immune checkpoint blockade (ICB) axis but have had limited success outside of recurrent/metastatic disease. Interleukin-7 (IL7) has been shown to be essential for effector T-cell survival, activation, and proliferation. Here, we show that IL7 in combination with radiotherapy (RT) is effective in activating CD8 + T-cells for reducing tumor growth. Our studies were conducted using both human papillomavirus related and unrelated orthotopic HNSCC murine models. Immune populations from the tumor, draining lymph nodes, and blood were compared between treatment groups and controls using flow cytometry, proteomics, immunofluorescence staining, and RNA sequencing. Treatment with RT and IL7 (RT + IL7) resulted in significant tumor growth reduction, high CD8 T-cell tumor infiltration, and increased proliferation of T-cell progenitors in the bone marrow. IL7 also expanded a memory-like subpopulation of CD8 T-cells. These results indicate that IL7 in combination with RT can serve as an effective immunotherapy strategy outside of the conventional ICB axis to drive the antitumor activity of CD8 T-cells.
... CD56 NK cell infiltration was associated with better survival rates in sinonasal squamous cell carcinoma and HNSCC, while tumors with smoking characteristics had lower immune infiltration and poorer survival rates. 45 Bochen et al. studied the relationship between vitamin D deficiency and the anti-tumor activity of NK cells in 463 HPV-positive HNSCC patients and found that vitamin D deficiency was more common in HNSCC patients and was associated with lymphatic metastasis, shorter overall survival, and changes in immune cell infiltration in the TME. 46 Further research suggests that vitamin D deficiency increases the cytotoxicity of NK cells against tumors, implying that appropriate vitamin D supplementation may improve patients' prognosis by promoting anti-tumor immune responses. ...
Objectives
Research progress of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) based on immune microenvironment.
Methods
This article preliminarily discusses the composition of immune microenvironment components and immune therapy and elaborates and analyzes the involvement and impact of T cells, B cells, natural killer (NK) cells, tumor-associated fibroblasts, and bone marrow-derived suppressor cells in HPV-positive HNSCC on tumor progression and prognosis. Furthermore, the application of immune-related therapies in HPV-positive HNSCC is explored.
Results
It is found that immune microenvironment research plays an important role in the pathogenesis and treatment of HPV-positive HNSCC.
Conclusions
Immune microenvironment research as an important means to explore tumors has played an important role in the study of HPV-positive HNSCC. We describe the biological significance of important components of HNSCC immune microenvironment by analyzing the effects of HNSCC immune microenvironment components and immunotherapy on HPV-positive HNSCC. May to provide new strategies for experimental research and clinical prevention and treatment of this disease.
... It has been observed that HPVpositive HNC and OPC had a significantly higher tumor infiltrating CD4 + , CD8 + , and CD3 + subsets and chemokine response [118,119]. HPV positive OPC are one of the most highly immune-cell infiltrated tumors that includes -CD3 + T cells, CD8 + T cells, Treg cells, B cells, and plasma cells, in comparison to HPV-OPC [120]. Additionally, ~64% of HPV+OPC have been shown to have HPV 16 specific infiltrating T cells as well [121]. ...
Human papillomavirus (HPV) is one the most common sexually transmitted infections (STI), spreading through direct sexual contact to oropharynx and anogenital regions. Although most infected individuals may be asymptomatic and naturally undergo viral clearance, in some individuals’ HPV infection causes carcinogenesis of the infected epithelia. HPV now accounts for over 70% of oropharyngeal carcinomas (OPC). Over 90% of these OPC are associated with HPV 16, one of the 14 high-risk subtypes. In recent years, HPV positive (HPV+) OPC has been one of the most rapidly rising cancers, by new cancer incidence rates, especially among men. They present some unique infection driven cellular and molecular features, in comparison to other head and neck carcinomas (HNC), constituting distinct preventive, therapeutic and prognostic strategies - with significant strides made in this area. However, HPV+OPC are routinely detected at a later stage, adding to the disease burden and overall survival. In this review, we provide a summary of HPV from a STI to malignant transformation, while also parsing through the immune response environment. We further collate key literature around infection sites, diagnostics and clinical management, while throwing light on the current state of epidemiology, transmission, screening and prevention strategies. Indeed, our improving understanding of the disease’s molecular biology has added some success to the prognostic outcomes of certain HPV+OPC across clinical trials examining targeted therapeutics and immunotherapy. This work is directed towards improving our current understanding of HPV and associated oncogenic landscape, to guide screening, early detection, triaging and further prevention and management strategies.
... By contrast, we found that Tregs were associated with DFS, especially in the hypopharynx subsite, but also contributed to favorable OS in the oral cavity subsite. In fact, the relationship between high Tregs recruitment and the prognosis of HNSCC remains controversial 12,25 . One of the reasons for Tregs being a good prognostic marker is that, depending on whether the tissue releases IL-12 and TGF-β, Tregs transform into two distinct immune subpopulations and thus have immunosuppressive or immune-boosting effects 26 . ...
... HPV-positive infection rates are highest in the oropharynx, while the larynx is less susceptible to infection 39 . Moreover, another explanation is that there is richer lymphoid tissue in the oropharynx than in the larynx 12 . ...
The immune infiltration profiles of the tumor microenvironment have effects on the prognosis of head and neck squamous cell carcinoma (HNSCC). Whereas, HNSCC is a heterogeneous group of tumors, but past work has not taken this into consideration. Herein, we investigate the associations between survival and the function of immune cells in different tumorigenic sites of HNSCC. 1149 samples of HNSCC were collected from publicly accessible databases. Based on gene expression data, CIBERSORTx was applied to determine the proportion of 22 immune cell subpopulations. In the Cox regression model, the associations between overall survival, disease-free survival, and immune cells were examined, modeling gene expression and immune cell proportion as quartiles. Consensus cluster analysis was utilized to uncover immune infiltration profiles. Regardless of tumor sites, CD8+ T cells and activated CD4 memory T cells were associated with favorable survival, while eosinophils were the opposite. The survival of the hypopharynx, oral cavity, and larynx subsites was somewhat affected by immune cells, while the survival of the oropharynx subsite potentially was the most impacted. High expression of TIGIT, CIITA, and CXCR6 was linked to better survival, mainly in the oropharynx subsite. Immune cell clusters with four distinct survival profiles were discovered, of which the cluster with a high CD8+ T cell content had a better prognosis. The immune-infiltration pattern is related to the survival of HNSCC to varying degrees depending on the tumor sites; forthcoming studies into immune-mediated infiltration profiles will lay the groundwork for treating HNSCC with precision therapy.
... HNSCC is the most common and high mortality cancer of the head and neck [29]. Conventional treatments (usually surgical resection, radiotherapy, and systemic therapy) have failed to achieve satisfactory overall results in HNSCC patients [30,31]. ...
... Head and neck tumors are highly immune-aggressive and severely immunosuppressive diseases 31,32 . Thus, we investigated the association between the degree of HNSC immune infiltration and FCGBP expression. ...
In head and neck squamous cell carcinoma (HNSC), chemoresistance is a major reason for poor prognosis. Nevertheless, there is a lack of validated biomarkers to screen for patients for categorical chemotherapy. Fc gamma binding protein (FCGBP) is a mucus protein associated with mucosal epithelial cells and has immunological functions that protect against tumors and metastasis. However, the effect of FCGBP on HNSC is unclear. In pan-cancer tissues, the expression of FCGBP and the survival status of patients were analyzed using information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Correlation analysis and Cox regression analysis were conducted to confirm the relationship and survival outcome. Bioinformatics analysis was utilized to predict the probable upstream non-coding RNA. FCGBP functioned as a potential tumor suppressor gene in HNSC. Notably, FCGBP expression was negatively correlated with enriched tumor-infiltrating macrophages and paclitaxel resistance. Cox regression with gene, clinical, and immune factors showed that FCGBP was a risk factor acting in an independent manner. In HNSC, the utmost possibly upstream non-coding RNA-related pathway of FCGBP was also discovered to be the PART1/AC007728.2/LINC00885/hsa-miR-877-5p/FCGBP axis. According to the present study, non-coding RNA-related low levels of FCGBP are a prognostic indicator and are linked to an HNSC-related immunosuppressive state.
