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.The genetic bases for predisposition, and neoplastic transformation, to cancer have been increasingly well described. However, it remains less clear how early, precancer cells employ these genetic alterations to acquire the characteristic features and properties (
1) of malignant disease. For example, studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent, metastatic head and neck squamous cell carcinoma (HNSC) therapy (
2–
4). This underscores the importance of immune modulation in these tumors, despite a still suboptimal overall response rate of less than 20% in advanced cancers. Immune response within tumors has been observed to be strongest at the earliest neoplastic stages, as reported recently in lung adenocarcinoma precursors (
5). As such, new, immune-based strategies could be developed to reduce the high global burden of HNSC, by intercepting the most common precursor of the most common HNSC presentation: HPV
− oral squamous cell carcinomas (
6–
8).Studies of chromosome somatic copy-number (CN) alteration (SCNA) profiles have reported the impact of 3p14, 9p21, or 17p13 loss in molecular models of HNSC progression (
9) and risk (
10–
15). Early studies reported that patients with oral precancers harboring 9p21 and/or 3p14 loss were at significantly greater cancer risk than those with retention at these loci (
10,
16). A comprehensive, prospective validation study examined the relative contribution of six candidate chromosome-arm regions. 9p21 loss had the greatest influence on cancer risk (
13). The mechanism underlying the association between CN and malignant transformation of precancers, however, is unclear (
17–
20). Studies of CN-altered neoplastic cells have shown that SCNAs can trigger a cytotoxic response in experimental precancer systems (
21,
22) but, paradoxically, were associated with immune evasion (
23) and suppression (
24) in computational studies of naturally occurring human cancers. The latter, in melanoma, found that nonresponders to PD-1 and CTLA-4 blockade had higher CN alteration and loss burdens, which correlated with immunologically cold tumors, characterized by cytotoxic-cell, marker, and metric reductions, and suppressive microenvironment cell, network, and signal increases (
23–
26). This SCNA-cold association was particularly strong in our previous, pan-The Cancer Genome Atlas (TCGA) computational study in HNSC (
23). These data point to a putative in vivo switch from immune hot-to-cold in the precancer–cancer transition, and raise the hypothesis that SCNAs in precursor lesions contribute to malignant transformation through genomic events and mechanisms that enable the acquisition of immune-suppressive, evasive properties. To test this hypothesis, we evaluated CN influence on immune profiles and outcomes in a large prospective oral precancer patient cohort, and HPV
− HNSC (tissue specimens and cell lines) and anti–PD-1–treated recurrent-disease cohorts.
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