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

Abstract

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.

Effects of the Mutant TP53 Reactivator APR-246 on Therapeutic Sensitivity of Pancreatic Cancer Cells in the Presence and Absence of WT-TP53

“…PDGFR-β expression is also suppressed in TP53-null cells due to TP73 binding NF-Y. In the presence of increased PDGFR-β expression, mut-TP53 can increase the extent of fibrosis and reduce the infiltration of cytotoxic CD8+ lymphocytes, which contributes to metastasis [ 42 ]. Mut-TP533 GOF mutations may promote a fibrotic tumor microenvironment, which suppresses the immune system to eliminate the PDAC.…”

“…Mut-TP533 GOF mutations may promote a fibrotic tumor microenvironment, which suppresses the immune system to eliminate the PDAC. This leads to a poor PDAC prognosis by promoting a more strenuous fibrotic tumor microenvironment [ 42 ].…”

Construction and Validation of a Combined Ferroptosis and Hypoxia Prognostic Signature for Hepatocellular Carcinoma

“…In addition, TP53 mutations can inhibit or induce ferroptosis due to differences in TP53 mutation sites (Jiang et al, 2015;Jennis et al, 2016;Thompson et al, 2020). Notably, TP53 missense mutations can also promote tumor immunosuppression and immune evasion by inhibiting CD8 + T cells and enhancing the activation of CAFs (Maddalena et al, 2021). Therefore, the inhibition state of ferroptosis and immunosuppression in the high-FHPS group may be related to the high mutation of TP53.…”

Promising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies

“…Involvement of mutant p53 in malignant inflammation associated with immune dysfunction and the ability of adaptive immune system to respond to mutations in p53 makes this protein an appropriate target for cancer immunotherapy ( 29 ). TP53 missense mutations in pancreatic ductal adenocarcinoma (PDAC) cells were found to increase the extent of fibrosis and reduce the infiltration of cytotoxic CD8+ T cells ( 30 ). The inhibition of mutant p53 functions may potentially sensitize PDAC tumors to anticancer treatments, including immunotherapy, therefore reduced infiltration of CD8+ T cells may augment the ability of PDAC tumors to evade the immune system.…”