posted on 2024-07-18, 10:53authored byJesse Boumelha, Andrea de Castro, Nourdine Bah, Hongui Cha, Sophie de Carné Trécesson, Sareena Rana, Mona Tomaschko, Panayiotis Anastasiou, Edurne Mugarza, Christopher Moore, Robert Goldstone, Phil East, Kevin Litchfield, Se-Hoon Lee, Miriam Molina-Arcas, Julian Downward
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.
Funding
Crick (Grant ID: CC2097, Grant title: Downward CC2097)
Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics)
European Research Council (Grant ID: 834692 - RASImmune, Grant title: ERC 834692 - RASImmune)
Wellcome Trust (Grant ID: 103799/A/14/Z, Grant title: WT 103799/A/14/Z)