TP53 missense mutations in PDAC are associated with enhanced fibrosis and an immunosuppressive microenvironment

Menée in vitro et à l'aide de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence le rôle de mutations faux-sens du gène TP53 dans le développement d'une fibrose tumorale et d'un microenvironnement immunosupresseur

Résumé en anglais

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, which is presently refractory to all available therapeutic strategies. PDAC tumors are characterized by a high degree of fibrosis, believed to be a major contributor to their therapy resistance. Mutations in theTP53 tumor suppressor gene are very frequent in PDAC. We now report that TP53 missense mutations, which lead to production of mutant p53 proteins, increase the extent of fibrosis and reduce the infiltration of cytotoxic CD8+ T cells. The inhibition of CD8+ T cell infiltration may augment the ability of PDAC tumors to evade the immune system. Hence, inhibition of the activities of mutant p53 may potentially sensitize PDAC tumors to anticancer treatments, including immunotherapy.Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, which is refractory to all currently available treatments and bears dismal prognosis. About 70% of all PDAC cases harbor mutations in the TP53 tumor suppressor gene. Many of those are missense mutations, resulting in abundant production of mutant p53 (mutp53) protein in the cancer cells. Analysis of human PDAC patient data from The Cancer Genome Atlas (TCGA) revealed a negative association between the presence of missense mutp53 and infiltration of CD8+ T cells into the tumor. Moreover, CD8+ T cell infiltration was negatively correlated with the expression of fibrosis-associated genes. Importantly, silencing of endogenous mutp53 in KPC cells, derived from mouse PDAC tumors driven by mutant Kras and mutp53, down-regulated fibrosis and elevated CD8+ T cell infiltration in the tumors arising upon orthotopic injection of these cells into the pancreas of syngeneic mice. Moreover, the tumors generated by mutp53-silenced KPC cells were markedly smaller than those elicited by mutp53-proficient control KPC cells. Altogether, our findings suggest that missense p53 mutations may contribute to worse PDAC prognosis by promoting a more vigorous fibrotic tumor microenvironment and impeding the ability of the immune system to eliminate the cancer cells.All study data are included in the article and/or supporting information.