In vivo CRISPR screen identifies KRAS-induced COX-2 as a driver of immune evasion and immunotherapy resistance in lung cancer

Oncogenic KRAS impairs anti-tumour immune responses, but effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identifies mechanisms by which oncogenic KRAS promotes immune evasion, most notably expression of immunosuppressive cyclooxygenase-2 (COX-2) in cancer cells. Oncogenic KRAS was a potent inducer of COX-2 in both mouse and human lung cancer which was suppressed using KRAS inhibitors. COX-2 acting via prostaglandin E2 (PGE2) promotes resistance to immune checkpoint blockade (ICB) in both mouse and human lung adenocarcinoma. Targeting COX-2/PGE2 remodelled the tumour microenvironment by inducing pro-inflammatory polarisation of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX-2 expression contributed to tumour relapse after prolonged KRAS inhibition. We propose testing COX-2/PGE2 pathway inhibitors in combination with KRAS G12C inhibition or ICB in patients with KRAS-mutant lung cancer. ### Competing Interest Statement J.D. has acted as a consultant for AstraZeneca, Jubilant, Theras, Roche and Vividion and has funded research agreements with Bristol Myers Squibb, Revolution Medicines and AstraZeneca. S.C.T has acted as a consultant for Revolution Medicines. K.L. has a patent on indel burden and CPI response pending and speaker fees from Roche tissue diagnostics, research funding from CRUK TDL/Ono/LifeArc alliance, and a consulting role with Monopteros Therapeutics. The other authors declare that they have no competing interests.