CRISPR-Cas9 screening identifies KRAS-induced COX-2 as a driver of immunotherapy resistance in lung cancer.

Abstract

Oncogenic KRAS impairs anti-tumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of how oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive cyclooxygenase-2 (COX-2) in cancer cells. Oncogenic KRAS potently induced COX-2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX-2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX-2/PGE2 remodeled the tumor microenvironment by inducing pro-inflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX-2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX-2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer.