Immune evasion in HPV <sup>−</sup> head and neck precancer–cancer transition is driven by an aneuploid switch involving chromosome 9p loss
William N. William, Xin Zhao, Joy J. Bianchi, Heather Lin, Pan Cheng, J. Jack Lee, Hannah Carter, Ludmil B. Alexandrov, Jim Abraham, David Spetzler, Steven M. Dubinett, Don W. Cleveland, Webster K. Cavenee, Teresa Davoli, Scott M. Lippman
Abstract
Significance 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 JAK2 - PD-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.