How the genetic landscape governs a tumor’s response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by KrasG12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.
Mutational signatures represent a footprint of tumor evolution and its endogenous and exogenous mutational processes. However, their functional impact on the proteome remains incompletely understood. We analysed the protein-coding impact of single base substitution signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) were strongly enriched in the signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes affect specific trinucleotide contexts to substitute serine and glutamic acid residues with stop codons. SGMs are enriched in cancer hallmark pathways and tumor suppressors such as TP53, FAT1, and APC. Tobacco-driven SGMs in lung cancer correlate with lifetime smoking history and highlight a preventable determinant of these harmful mutations. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes contribute to protein loss-of-function, oncogenesis, and tumor heterogeneity, providing potential translational and mechanistic insights.
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