Despite the dramatic clinical success of cancer immunotherapy with PD-1 checkpoint blockade, most patients do not experience sustained clinical benefit from treatment, suggesting that additional therapeutic strategies are needed. To discover new immunotherapy targets, we developed a pooled, loss-of-function in vivo genetic screening approach using CRISPR/Cas9 genome editing in mouse transplantable tumors treated with vaccination and PD-1 checkpoint blockade. We tested 2,400 genes expressed by melanoma cells for those that synergize with or cause resistance to checkpoint blockade, and recovered the known immune evasion molecules, PD-L1 and CD47. Loss of function of genes required to sense interferon-γ caused resistance to immunotherapy. Deletion of Ptpn2, a pleotropic protein tyrosine phosphatase, improved response to immunotherapy. Cellular, biochemical, transcriptional, and genetic epistasis experiments demonstrated that loss of function of Ptpn2 sensitizes tumors to immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. Thus, strategies that increase interferon-γ sensing by tumor cells could improve the efficacy of immunotherapy. More generally, in vivo genetic screens in tumor models can identify new immunotherapy targets, model resistance mechanisms, and may accelerate the rational selection of combination immunotherapy.

Citation Format: W Nicholas Haining. In vivo genetic screens for genes that modulate tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY40-01.