MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome du poumon avec mutation du gène KRAS, cette étude met en évidence un mécanisme par lequel la déficience de la kinase LKB1 dans les cellules cancéreuses augmente la sécrétion de lactate via le transporteur MCT4 et favorise la suppression de l'immunité antitumorale

Résumé en anglais

Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.