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At the Crossroads of Molecular Biology and Immunology: Molecular Pathways for Immunological Targeting of Head and Neck Squamous Cell Carcinoma.

ABSTRACT: Background: Recent advances in immunotherapy for head and neck squamous cell carcinoma (HNSCC) have led to implementation of anti-programmed death receptor 1 (PD-1) immunotherapy to standard of care for recurrent/metastatic HNSCC. However, the majority of tumors do not respond to these therapies, indicating that these tumors are not immunogenic or other immunosuppressive mechanisms might be at play. Aim: Given their role in carcinogenesis as well as in immune modulation, we discuss the relation between the STAT3, PI3K/AKT/mTOR and Wnt signaling pathways to identify potential targets to empower the immune response against HNSCC. Results: We focused on three pathways. First, STAT3 is often overactivated in HNSCC and induces the secretion of immunosuppressive cytokines, thereby promoting recruitment of immune suppressive regulatory T cells and myeloid-derived suppressor cells to the tumor microenvironment (TME) while hampering the development of dendritic cells. Second, PI3K/AKT/mTOR mutational activation results in increased tumor proliferation but could also be important in HNSCC immune evasion due to the downregulation of components in the antigen-processing machinery. Third, canonical Wnt signaling is overactivated in >20% of HNSCC and could be an interesting pleotropic target since it is related to increased tumor cell proliferation and the development of an immunosuppressive HNSCC TME. Conclusion: The molecular pathology of HNSCC is complex and heterogeneous, varying between sites and disease etiology (i.e., HPV). The in HNSCC widely affected signaling pathways STAT3, PI3K/AKT/mTOR and Wnt are implicated in some of the very mechanisms underlying immune evasion of HNSCC, thereby representing promising targets to possibly facilitate immunotherapy response.

SUBMITTER: Wondergem NE

PROVIDER: S-EPMC8757702 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Head and neck squamous cell carcinoma (HNSCC) arises from the epithelial lining of the oral cavity, hypopharynx, oropharynx, and larynx. There are several potential risk factors that cause the generation of HNSCC, including cigarette smoking, alcohol consumption, betel quid chewing, inadequate nutrition, poor oral hygiene, HPV and Epstein-Barr virus, and Candida albicans infections. HNSCC has causative links to both environmental factors and genetic mutations, with the latter playing a more critical role in cancer progression. These molecular changes to epithelial cells include the inactivation of cancer suppressor genes and proto-oncogenes overexpression, resulting in tumour cell proliferation and distant metastasis. HNSCC patients have impaired dendritic cell (DC) and natural killer (NK) cell functions, increased production of higher immune-suppressive molecules, loss of regulatory T cells and co-stimulatory molecules and major histocompatibility complex (MHC) class Ι molecules, lower number of lymphocyte subsets, and a poor response to antigen-presenting cells. At present, the standard treatment modalities for HNSCC patients include surgery, chemotherapy and radiotherapy, and combinatorial therapy. Despite advances in the development of novel treatment modalities over the last few decades, survival rates of HNSCC patients have not increased. To establish effective immunotherapies, a greater understanding of interactions between the immune system and HNSCC is required, and there is a particular need to develop novel therapeutic options. A therapeutic cancer vaccine has been proposed as a promising method to improve outcome by inducing a powerful adaptive immune response that leads to cancer cell elimination. Compared with other vaccines, peptide cancer vaccines are more robust and specific. In the past few years, there have been remarkable achievements in peptide-based vaccines for HNSCC patients. Here, we summarize the latest molecular alterations in HNSCC, explore the immune response to HNSCC, and discuss the latest developments in peptide-based cancer vaccine strategies. This review highlights areas for valuable future research focusing on peptide-based cancer vaccines.

Project description:Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either "light" or "dark" to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35-38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.

Project description:ObjectiveThis study is aimed at investigating the regulating mechanisms of the interferon regulatory factor (IRF) family genes in head and neck squamous cell carcinoma.MethodsBased on the HNSC data in the 'The Cancer Genome Atlas (TCGA)' database, the expression pattern of IRF family genes was investigated. The association of IRFs family genes and survival outcomes were analyzed by Kaplan-Meier plotter web portal. The relation of IRF genes and tumor stages was evaluated by using stage plots and based on GEPIA portal. 50 genes interacting with IRFs were identified using the NetworkAnalyst's protein-protein interaction (PPI) network construction tool. The top 200 correlated genes with similar expression patterns in HNSC were obtained by the similar gene detection module of GEPIA. Furthermore, functional enrichment analysis was performed to determine the biological functions enriched by the interacting and correlated genes. The potential implication of IRFs in tumor immunity was investigated in terms of tumor-infiltrating immune cells, a pair of immune checkpoint genes (CD274 and PDCD1), and ESTIMATE-Stromal-Immune score.ResultsThe unpaired sample analysis shows that all of the IRF family genes were highly expressed in HNSC tumor samples compared to control samples. The survival analysis results showed that the overexpression of IRF1, IRF4, IRF5, IRF6, IRF8, and IRF9 was associated with better overall survival in HNSC, while the other IRFs genes (IRF2, IRF3. and IRF7) did not show prognostic values for overall survival outcome of HNSC. Four genes (STAT1, STAT2, FOXP3, and SPI1) were overlapping among 50 interacted genes in the PPI network and top 200 correlated genes identified by GEPIA. The 50 interacting genes in the PPI network and top 200 correlated genes were integrated into 246 genes. These 246 genes were found to be overrepresented in multiple KEGG pathways, e.g., Th17 cell differentiation, T cell receptor signaling pathway, cytokine-cytokine receptor interaction, natural killer (NK) cell-mediated cytotoxicity, FOXO signaling, PI3K-Akt signaling, and ErbB signaling. Most correlations between IRF gene members and TIICs were positive. The strongest positive correlation was identified between IRF8 and T cells (r = 0.849, p < 0.001). The majority of correlation between IRF family genes and ESTIMATE-Stromal-Immune score was found to be positive. The highest positive correlation was found to be between IRF8 and Immune score (r = 0.874, p = 1.09E - 158). Most correlations between IRFs and two immunoinhibitor genes (CD274 and PDCD1) were positive. IRF1 and PDCD1 were found to show the highest positive correlation (r = 0.764, p < 2.2e - 16).ConclusionsThe current analysis showed IRFs were differentially expressed in HNSC, indicated significant prognostic values, were involved in tumor immunity-related signaling pathways, and significantly regulated tumor-infiltrating immune cells. IRF family genes could be potential therapeutic biomarkers in targeting tumor immunity of head and neck cancer.

Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.

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At the Crossroads of Molecular Biology and Immunology: Molecular Pathways for Immunological Targeting of Head and Neck Squamous Cell Carcinoma.

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