Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Veigas F
PROVIDER: S-EPMC7957692 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:With the understanding of the complex interaction between the tumour microenvironment and immunotherapy, there is increasing interest in the role of immune regulators in the treatment of head and neck squamous cell carcinoma (HNSCC). Activation of T cells and immune checkpoint molecules is important for the immune response to cancers. Immune checkpoint molecules include cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), T-cell immunoglobulin mucin protein 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), T cell immunoglobin and immunoreceptor tyrosine-based inhibitory motif (TIGIT), glucocorticoid-induced tumour necrosis factor receptor (GITR) and V-domain Ig suppressor of T cell activation (VISTA). Many clinical trials using checkpoint inhibitors, as both monotherapies and combination therapies, have been initiated targeting these immune checkpoint molecules. This review summarizes the functional mechanism and use of various immune checkpoint molecules in HNSCC, including monotherapies and combination therapies, and provides better treatment options for patients with HNSCC.
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Project description:Quantitative (iTRAQ 4-plex) proteomic analysis of progressive head and neck cancers
2022-03-01 | PXD001438 | Pride
Project description:Tumor immune infiltration cells (TIICs) are highly heterogeneous, not only in different cancer subtypes but also within different cancer regions. We conducted the Cell-type Identification using Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method. We assessed the relative proportions of 22 TIICs in HNSC using publicly available TCGA transcriptional datasets, analyzed the proportions of TIICs between HNSC tissues and normal tissues, along with accompanying clinicopathological data, and the impact of TIICs on clinical outcome. After the filter criteria, a total of 395 patients were included in the analysis. We found significant differences in naïve B cells, monocytes, resting mast cells, activated mast cells, CD8+ T cells, and M0 macrophages between HNSC tissues and adjacent non-cancer tissues. We also found that some TIIC subgroups were significantly associated with clinical parameters. Moreover, the patients with low Tregs fraction had worse OS and DFS than those with high Tregs fraction. However, low M0 macrophages fraction was associated with better OS and DFS in HNSC patients. Moreover, Tregs and M0 macrophages are likely to be important determinants of prognosis, which may serve as a potential immunotherapy target for HNSC. Then, we screened the immune-related differentially expressed genes (DEGs), performed the GO and KEGG enrichment analysis, constructed the protein-protein interaction network, and screened the prognosis-related hub genes in HNSC. However, further clinical investigation and basic experiments are needed to validate our results, and uncover the molecular mechanisms interlinking TIICs in HNSC and their roles in prognosis and therapy.
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Project description:BackgroundLong noncoding RNAs (lncRNAs) play a critical role in innate and adaptive immune responses. Thus, we aimed to identify ideal subtypes for head and neck squamous cell carcinoma (HNSCC) based on immune-related lncRNAs.MethodsTCGA HNSCC cohort was divided into two datasets (training and validation dataset), and 960 previously characterized immune-related lncRNAs were extracted for non-negative matrix factorization analysis. We characterized our HNSCC subtypes based on biological behaviors, immune landscape and response to immunotherapy in both training and validation cohort. A lncRNA-signature was generated to predict our HNSCC subtypes, and essential lncRNAs involved in tumor microenvironment (TME) were identified.ResultsWe developed and validated two HNSCC subtypes (C1 and C2) based on the 70 lncRNAs in the training and validation cohort. C2 subtype displayed good prognosis, high immune cell infiltration, immune-related genes expression and sensitivity to PD-1 blockade. C1 subtype was associated with high activity of mTORC1 signaling and glycolysis as well as high fraction of inactive immune cells. Finally, we generated a 31-lncRNA signature that could predict our above subtypes with high accurate. Additionally, TRG-AS1 was identified as the essential lncRNA involving TME formation. Knockdown of TRG-AS1 inhibited the expression of HLA-A, HLA-B, HLA-C, CXCL9, CXCL10 and CXCL11. High expression of TRG-AS1 indicated a favorable prognosis in HNSCC and anti-PD-L1 cohort (IMvigor210).ConclusionsOur study establishes a novel HNSCC classification on the basis of 31-lncRNA, helping to identify beneficiaries for anti-PD-1 treatment. In addition, a critical lncRNA TRG-AS1 is identified as a new potential prognosis biomarker as well as therapeutic target.
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Project description:Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.
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Project description:ObjectivesIn this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors.Materials and methodsTwo SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status.ResultsTCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the β-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications.ConclusionsOur findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.
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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.
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Project description:Head and neck squamous cell carcinomas (HNSCCs) are a type of common malignant tumor, mainly manifesting as oropharyngeal, oral cavity, laryngopharyngeal, hypopharyngeal, and laryngeal cancers. These highly aggressive malignant tumors reportedly affect more than 830,000 patients worldwide every year. Currently, the main treatments for HNSCC include surgery, radiotherapy, chemotherapy, and immunotherapy, as well as combination therapy. However, the overall 5-year survival rate of HNSCC has remained 50%, and it has not significantly improved in the past 10 years. Previous studies have shown that the tumor microenvironment (TME) plays a crucial role in the recurrence, metastasis, and drug resistance of patients with HNSCC. In this review, we summarize the role of anti-tumor and pro-tumor immune cells, as well as extracellular components in the TME of HNSCC. We also discuss classical HNSCC immunotherapy and highlight examples of clinical trials using CTLA-4 inhibitors and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1)-related combination therapies. We also outline some molecules in the TME known to regulate immunosuppressive cells. Furthermore, the role and underlying mechanism of radiation therapy on the TME, immune cells, and immune response are discussed.
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Project description:The immune response within the tumor microenvironment plays a key role in tumorigenesis and determines the clinical outcomes of head and neck squamous cell carcinoma (HNSCC). However, to date, very limited robust and reliable immunological biomarkers have been developed that are capable of estimating prognosis in HNSCC patients. In this study, we aimed to identify the effects of novel immune-related gene signatures (IRGs) that can predict HNSCC prognosis. Based on gene expression profiles and clinical data of HNSCC patient cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, a total of 439 highly variable expressed immune-related genes (including 239 upregulated and 200 downregulated genes) were identified by using differential gene expression analysis. Pathway enrichment analysis indicated that these immune-related differentially expressed genes were enriched in inflammatory functions. After process screening in the training TCGA cohort, six immune-related genes (PLAU, STC2, TNFRSF4, PDGFA, DKK1, and CHGB) were significantly associated with overall survival (OS) based on the LASSO Cox regression model. Integrating these genes with clinicopathological features, a multivariable model was built and suggested better performance in determining patients' OS in the testing cohort, and the independent validation cohort. In conclusion, a well-established model encompassing both immune-related gene signatures and clinicopathological factors would serve as a promising tool for the prognostic prediction of HNSCC.
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Project description:Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease.
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