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

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 prese...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2021-05, Vol.118 (19), p.1
Main Authors: William, Jr, 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
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Summary: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 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 - 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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2022655118