Deciphering head and neck cancer microenvironment: Single‐cell and spatial transcriptomics reveals human papillomavirus‐associated differences
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE281978 | GEO | 2024/11/20
REPOSITORIES: GEO
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Project description:We reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification, and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors.
2024-09-06 | PXD055003 | Pride
Project description:Head and neck squamous cell carcinomas (HNSCC) driven by human papillomavirus (HPV) generally have a more favourable prognosis. We hypothesized that HPV-positive HNSCC may be identified based on a miRNA signature according to their specific molecular pathogenesis and are characterized by a unique transcriptome compared to HPV-negative HNSCC. We characterized the miRNA-expression patterns of the tumors from 229 head and neck squamous cell carcinoma patients by Agilent miRNA microarrays in order to define a HPV-predicting miRNA signature.
2023-05-10 | GSE175509 | GEO
Project description:ABSTRACT Two major subgroups of head and neck squamous cell carcinomas (HNSCC) are currently distinguished based on etiology and pattern of genetic alterations; tumors with biologically active human papillomavirus (HPV) and tumors without. It is at present unclear whether additional genetically distinct subgroups exist within HPV-negative HNSCC. Aim of this study is to genetically classify HNSCC without HPV involvement and to correlate the genetically defined classes to tumor and patient characteristics. By means of array comparative genomic hybridization (aCGH) we determined DNA copy number variation in thirty-nine HPV-negative, but further unselected HNSCC. Unsupervised analysis of aCGH data distinguished two genetic groups in HPV-negative HNSCC, one characterized by a low level of chromosomal alterations (N=9), and another by a high level of chromosomal alterations (N=30). Absence of chromosomal aberrations was significantly associated with wild-type TP53, a low level of alcohol consumption, a female gender and a better prognosis. The tumors were negative for microsatellite instability. The discovery of this new class of HNSCC with unique genetic and clinical characteristics has important consequences for future basic and clinical studies. All DNAs are isolated from fresh frozen HNSCC specimen. All tissue specimens were microdissected to obtain at least 90% tumor DNA. All sampels are hybridized against a pool of reference DNA of normal individuals of the opposite gender.
2009-03-11 | E-GEOD-11929 | biostudies-arrayexpress
Project description:Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide and the human papillomavirus (HPVP+P)-driven subtype is the fastest rising in North America. Although most cases of HPV+ HNSCC respond to radiation and chemotherapy in combination with surgery, up to 20% of patients recur after primary treatment with poor prognosis. To gain insights into the mechanism of recurrence to inform patient stratification and precision treatment, we carried out RNA-seq analysis on 43 HPV+ HNSCC specimens, of which 15, including 7 recurrent tumors, were analyzed by quantitative mass spectrometry. The proteome and phosphoproteome, but not the transcriptome, were found to be distinct between the recurrent and non-recurrent tumors. Specifically, recurrent tumors featured a pro-fibrotic and immune suppressive tumor microenvironment (TME) characterized with more abundant cancer associated fibroblasts, extracellular matrix (ECM), neutrophils and suppressive myeloid cells, increased potential for epithelial-mesenchymal transition and defective T cell function, accompanied by aberrant changes in the corresponding signaling pathways. Mechanistically, kinome reprogramming played a pivotal role in mediating recurrence through regulating TME remodelling, cytoskeletal reorganization, cell adhesion, neutrophil function, and coagulation. Besides providing systems-level insights into the molecular basis of recurrence, our work led to the identification of numerous mechanism-based biomarkers and therapeutic targets that may aid future endeavours of developing prognostic biomarkers and precision medicine for recurrent HPV+ HNSCC.
2022-06-01 | PXD030343 | Pride
Project description:ABSTRACT Two major subgroups of head and neck squamous cell carcinomas (HNSCC) are currently distinguished based on etiology and pattern of genetic alterations; tumors with biologically active human papillomavirus (HPV) and tumors without. It is at present unclear whether additional genetically distinct subgroups exist within HPV-negative HNSCC. Aim of this study is to genetically classify HNSCC without HPV involvement and to correlate the genetically defined classes to tumor and patient characteristics. By means of array comparative genomic hybridization (aCGH) we determined DNA copy number variation in thirty-nine HPV-negative, but further unselected HNSCC. Unsupervised analysis of aCGH data distinguished two genetic groups in HPV-negative HNSCC, one characterized by a low level of chromosomal alterations (N=9), and another by a high level of chromosomal alterations (N=30). Absence of chromosomal aberrations was significantly associated with wild-type TP53, a low level of alcohol consumption, a female gender and a better prognosis. The tumors were negative for microsatellite instability. The discovery of this new class of HNSCC with unique genetic and clinical characteristics has important consequences for future basic and clinical studies.
2009-03-12 | GSE11929 | GEO
Project description:Human cancer cell lines are the most frequently used preclinical models in the study of cancer biology and the development of therapeutics. Although anatomically diverse, human papillomavirus (HPV)-driven cancers have a common etiology and similar mutations that overlap with but are distinct from those found in HPV-negative cancers. Building on prior studies that have characterized subsets of head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESC) cell lines separately, we performed genomic, viral gene expression, and viral integration analyses on 74 cell lines that include all readily-available HPV-positive (9 HNSCC, 8 CESC) and CESC (8 HPV-positive, 2 HPV-negative) cell lines and 55 HPV-negative HNSCC cell lines. We used over 700 human tumors for comparison. Mutation patterns in the cell lines were similar to those of human tumors. We confirmed HPV viral protein and mRNA expression in the HPV-positive cell lines. We found HPV types in three CESC cell lines that are distinct from those previously reported. We found that cell lines and tumors had similar patterns of viral gene expression; there were few sites of recurrent HPV integration. As seen in tumors, HPV integration did appear to alter host gene expression in cell lines. The HPV-positive cell lines had higher levels of p16 and lower levels of Rb protein expression than did the HPV-negative lines. Although the number of HPV-positive cell lines is limited, our results suggest that these cell lines represent suitable models for studying HNSCC and CESC, both of which are common and lethal.
2018-11-15 | GSE122512 | GEO
Project description:Oncogene expressing human papillomavirus type 16 (HPV16) is found in a subset of head and neck squamous cell carcinomas (HNSCC). HPV16 drives carcinogenesis by inactivating p53 and pRb with the viral oncoproteins E6 and E7, reflected by a low level of mutations in TP53 and allelic loss at 3p, 9p and 17p, genetic changes frequently found in HNSCCs of non-viral etiology. We hypothesize that two pathways to HNSCC exist: one determined by HPV16 and one by environmental carcinogens. To define the critical genetic events in these two pathways, we now present a detailed genome analysis of HNSCC with and without HPV16 involvement by employing high resolution micro-array comparative genomic hybridization. Four regions showed alterations in HPV-negative tumors that were absent in HPV-positive tumors: losses at 3p11.2-26.3, 5q11.2-35.2, 9p21.1-24, and gains/amplifications at 11q12.1-13.4. Also, HPV16-negative tumors demonstrated loss at 18q12.1-23, in contrast to gain in HPV16-positive tumors. Seven regions were altered at high frequency (>33%) in both groups: gains at 3q22.2-qter, 5p15.2-pter, 8p11.2-qter, 9q22-34.1, 20p-20q and losses at 11q14.1-qter and 13q11-33. These data show that HNSCC arising by environmental carcinogens are characterized by genetic alterations that differ from those observed in HPV16-induced HNSCC, and most likely occur early in carcinogenesis. A number of genetic changes are shared in both tumor groups and can be considered crucial in the later stages of HNSCC progression. Tumor DNA is isolated from fresh frozen tissue. Tumor DNA is enriched by microdissection. Reference DNA is isolated from blood of normal individuals of the opposit gender.
2009-05-26 | E-GEOD-11931 | biostudies-arrayexpress
Project description:Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral CD45+ immune populations from HPV– and HPV+ HNSCC and healthy donors. A spectrum of transcriptional signatures in immune lineages ranging from similar to highly divergent was present in the tumor microenvironments (TME) in HPV– and HPV+ HNSCC. CD8+ and regulatory CD4+ T cells were similar in HPV– and HPV+ HNSCC, compared to significant differences between helper CD4+ T cells, B cells and myeloid cells. Further dissection of the major immune lineages identified unique cell states and differentiation trajectories. We contextualized our results by performing multispectral immunofluorescence and evaluating putative cell-cell communication based on spatial proximity, and found longer progression free survival in patients with enrichment of a CD4+ T follicular helper cell signature.
2019-11-13 | GSE139324 | GEO
Project description:Human papillomavirus (HPV) positive HNSCC patients generally have a favorable survival and promising responsiveness to radiotherapy, chemoradiotherapy and checkpoint blockades. However, HPV negative patients, the majority of HNSCC patients, have been largely overlooked. Cell death has been involved in the therapeutic resistance of cancers. We constructed a cell death index (CDI), based on autophagy, apoptosis and pyroptosis related genes, to predict the prognosis for HNSCC using TCGA dataset, and validated in a cohort from Qilu Hospital of Shandong University. We performed RNA sequencing of 28 paraffin-embedded tissue from HNSCC patients and determined HPV status by immunohistochemistry of p16. We found that CDI was an independent prognostic indicator for overall survival. Notably, the prognostic value of CDI was more profound in HPV negative HNSCC patients compared with those with HPV positivity.
2023-02-07 | GSE208576 | GEO
Project description:Oncogene expressing human papillomavirus type 16 (HPV16) is found in a subset of head and neck squamous cell carcinomas (HNSCC). HPV16 drives carcinogenesis by inactivating p53 and pRb with the viral oncoproteins E6 and E7, reflected by a low level of mutations in TP53 and allelic loss at 3p, 9p and 17p, genetic changes frequently found in HNSCCs of non-viral etiology. We hypothesize that two pathways to HNSCC exist: one determined by HPV16 and one by environmental carcinogens. To define the critical genetic events in these two pathways, we now present a detailed genome analysis of HNSCC with and without HPV16 involvement by employing high resolution micro-array comparative genomic hybridization. Four regions showed alterations in HPV-negative tumors that were absent in HPV-positive tumors: losses at 3p11.2-26.3, 5q11.2-35.2, 9p21.1-24, and gains/amplifications at 11q12.1-13.4. Also, HPV16-negative tumors demonstrated loss at 18q12.1-23, in contrast to gain in HPV16-positive tumors. Seven regions were altered at high frequency (>33%) in both groups: gains at 3q22.2-qter, 5p15.2-pter, 8p11.2-qter, 9q22-34.1, 20p-20q and losses at 11q14.1-qter and 13q11-33. These data show that HNSCC arising by environmental carcinogens are characterized by genetic alterations that differ from those observed in HPV16-induced HNSCC, and most likely occur early in carcinogenesis. A number of genetic changes are shared in both tumor groups and can be considered crucial in the later stages of HNSCC progression.
2009-05-26 | GSE11931 | GEO