Immune evasion in HPV- head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss.
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| Abstract |
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 associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm 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.
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| Authors | William N William Jr, Xin Zhao, Joy J Bianchi, Heather Y Lin, Pan Cheng, J Jack Lee, Hannah Carter, Ludmil B Alexandrov, Jim P Abraham, David B Spetzler, Steven M Dubinett, Don W Cleveland, Webster Cavenee, Teresa Davoli, Scott M Lippman |
| Journal | Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 19 (05 11 2021) ISSN: 1091-6490 [Electronic] United States |
| PMID | 33952700 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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