Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression
Menée à l'aide de modèles murins, cette étude suggère l'intérêt d'une stratégie thérapeutique basée sur l'inhibition d'une voie de signalisation activant p38 dans les lymphocytes T infiltrant les tumeurs d'un adénocarcinome canalaire du pancréas
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323+ T cells was associated with large numbers of tumor necrosis factor (TNF)-
α
− and interleukin (IL)-17–producing CD4+ tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4+ T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell–deficient mice. Notably, a plasma membrane–permeable peptide derived from GADD45-
α, the naturally occurring inhibitor of p38 pY323+ (ref. 7), reduced CD4+ TIL production of TNF-α, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4+ TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.