Immune evasion in HPV – head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss


William N William Jr 1 2, Xin Zhao 3, Joy J Bianchi 3, Heather Y Lin 4, Pan Cheng 3, J Jack Lee 4, Hannah Carter 5 6, Ludmil B Alexandrov 5 7 8, Jim P Abraham 9, David B Spetzler 9, Steven M Dubinett 10, Don W Cleveland 5 7 11, Webster Cavenee 12 6 11, Teresa Davoli 13, Scott M Lippman 14 5 6


We report somatic copy-number alterations (SCNAs) that contribute to an immune microenvironment switch during human papillomavirus-negative head and neck cancer (HNSC) development. Specific and nonspecific SCNA levels were examined in a large prospective oral precancer (188 patients) cohort, 2 HNSC (343, 196 patients) cohorts, and 32 cell lines. Chromosome 9p21.3 loss in precursor lesions, the genomic driver of malignant transition, was enhanced by cumulative 9p-arm gene-dosage decreases, cell-intrinsic senescence suppression, and extrinsic decreases in chemokine, cytokine, and NF-κB pathways. Furthermore, 9p-arm loss and JAK2PD-L1 codeletion were associated with PD-1 inhibitor resistance. These data reveal an oncogenic immune paradox, aneuploid checkpoint to neoplastic transformation, and immune interception and therapeutic strategies for HPV HNSC and possibly other CN-driven tumors or diseases.

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