Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T Cells in KRAS-Mutant Cholangiocarcinoma
Menée à l'aide de modèles murins de cholangiocarcinome intrahépatique, de fragments tumoraux d'origine humaine et d'une analyse multiomique, cette étude met en évidence un mécanisme par lequel la mutation de KRAS supprime la capacité antitumorale des lymphocytes T en favorisant la production de prostaglandine E2 dans les cellules cancéreuses, l'augmentation de la consommation d'acide arachidonique et l'expression de la cyclo-oxygénase COX-2 dans les cellules myéloïdes polynucléaires suppressives puis démontre les effets antitumoraux d'une stratégie thérapeutique ciblant conjointement PD-1 et l'axe
Metabolic reprogramming within the tumor microenvironment (TME) impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multiomics-based metabolic subtyping in intrahepatic cholangiocarcinoma, we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both cyclooxygenase/arachidonic acid (COX/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation–mediated NF-
κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the TME. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2, in turn, enhances AA uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via the prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2
–PGE2–EP4 axis, combined with anti–PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.
Cancer Discovery , résumé, 2026