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

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 mu-tations, 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. Im-portantly, 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.

Automated summary

Missense p53 mutations in PDAC patients can suppress CD8(+) T cell infiltration into tumors and hinder the immune system’s ability to eliminate cancer cells. Silencing mutp53 can reduce tumor size and fibrotic response.