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Comprehensive Characterization of the Tumor  Microenvironment for Assessing Immunotherapy Response in Patients with  Head and Neck Squamous Cell Carcinoma

Background: The tumor microenvironment (TME) constitutes a complex milieu of cells and cytokines that maintain equilibrium between tumor progression and prognosis. However, comprehensive analysis of the TME and its clinical significance in head and neck squamous cell carcinoma (HNSCC) remains to be reported. 
 
Methods: Based on large-scale RNA sequencing data of HNSCC patients from The Cancer Genome Atlas database, we analysed subpopulations of infiltrating immune cells. An unsupervised clustering method was used to evaluate TME infiltration pattern (TME score); TME phenotypes were systematically correlated with genomic characteristics and clinicopathological features of HNSCC. Three TME phenotypes were defined, and TME score was obtained using principal component analysis algorithms. Mutational signatures were analysed based on single nucleotide variants (SNVs) and copy number variations (CNVs). 
 
Findings: TME signature genes were characterized by immunoglobulin complex and antigen receptor-mediated signalling pathway. Allograft rejection, inflammatory response, and reactive oxygen species pathway were observed in the low TME score subtype, which were considered immunosuppressive and potentially responsible for significantly worse prognosis. Tumor mutation burden based on SNVs and CNVs was involved in immune regulation. 
 
Interpretation: Our data provide clarity on the comprehensive landscape of interactions between clinical characteristics of HNSCC and tumor-infiltrating immune cells. We suggest that TME score is a novel biomarker that can predict immunotherapy response in HNSCC patients. 
 
Funding Statement: This study was supported by grants from the Science and Technology Program of Guangzhou (201803010024), Social Science and Technology Development Key Project of Dongguan (201750715046462), Guangzhou Key Medical Discipline Construction Project Fund (B195002004042), and Open Funds of State Key Laboratory of Oncology in South China (KY013711). 
 
Declaration of Interests: The authors stated: "None." 
 
Ethics Approval Statement: This study was approved by the Ethics Committees of Cancer Hospital & Institute of Guangzhou Medical University and performed in accordance with guidelines established by the Declaration of Helsinki.