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

Significance 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 the TP53 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.