Abstract

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, we performed CRISPR/Cas9 screens directly in mouse lung cancer models. We recovered the known immune evasion factors Stat1 and Serpinb9 and identified the cancer testis antigen Adam2 as a new 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 Pd-l1, 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. Corresponding clinical data of LUAD patients from TCGA show that ADAM2 is associated with significantly lower IFN I/II and TNF alpha signaling pathways and thus recapitulate findings obtained from the mouse experiments of LUAD. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.