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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-05, Vol.118 (19), p.1-12
• Main Authors: William, William N., Zhao, Xin, Bianchi, Joy J., Lin, Heather Y., Cheng, Pan, Lee, J. Jack, Carter, Hannah, Alexandrov, Ludmil B., Abraham, Jim P., Spetzler, David B., Dubinett, Steven M., Cleveland, Don W., Cavenee, Webster, Davoli, Teresa, Lippman, Scott M.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Aneuploidy; B7-H1 Antigen; Biological Sciences; Cancer; CD3 antigen; CD3 Complex; CD8 antigen; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chemokines; Chromosome 9; Chromosome Deletion; Chromosomes; Clonal deletion; Cytokines; Cytotoxicity; Deletion; Depletion; DNA Copy Number Variations; Dosage; Epistasis; Gene Expression Regulation, Neoplastic; Genes, p53 - genetics; Head & neck cancer; Head and Neck Neoplasms - genetics; Human papillomavirus; Humans; Immune evasion; Immune Evasion - genetics; Immunotherapy; Infiltration; Interception; Janus Kinase 2; Lymphocytes; Lymphocytes T; Metastases; Microenvironments; Middle Aged; NF-κB protein; p53 Protein; Papillomavirus Infections - genetics; PD-1 protein; PD-L1 protein; Senescence; T-Lymphocytes, Cytotoxic; Trisomy; Tumor Microenvironment; Tumorigenesis; Tumors; Young Adult; γ-Interferon
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2022655118

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV⁻) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3⁺ and CD8⁺ T cell microenvironments in precancer (mostly CD3⁺, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associatedwith increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9parm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV⁻ HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.