Regulation of cytotoxic T-cell responses by p53 in cancer

Abstract

An intriguing aspect of the tumor suppressor p53 is its ability to communicate to the adaptive immune system and control the cytotoxic T-lymphocyte (CTL) response to cancer cells. Wild-type p53 (wtp53) communicates with CTLs through proteins involved in the major histocompatibility complex (MHC) class I antigen presentation pathway [e.g., transporter associated with antigen processing 1 (TAP1) and endoplasmic reticulum amino peptidase 1 (ERAP1)], the apoptosis signal receptor Fas/APO-1, and the inhibitory immune-checkpoint programmed death-ligand 1 (PD-L1). The presence of wtp53 in cancer cells ultimately promotes effector CTL-induced tumor cell death. Analogously, wtp53 in tumors unleashes the CTL response via inhibition of PD-L1 and enhances their effectiveness by upregulating Fas/APO-1 and MHC I. Given that p53 is mutated in approximately 50% of human cancers and also impacts the immunoreactivity of cancer cells, a significant number of patients can be affected by the impaired CTL response that results from non-functional p53. An attenuated CTL response due to p53 mutations could decrease response rates to immunotherapeutic drugs, leading to poor patient prognoses. This review article will summarize how p53 can regulate the cell-mediated adaptive immune response to cancer.

A tumor‐targeting nanomedicine carrying the p53 gene crosses the blood–brain barrier and enhances anti‐PD‐1 immunotherapy in mouse models of glioblastoma

“…Importantly, the SGT‐53 plus anti‐PD‐1 combination treatment restored T‐cell effector function and increased CTLs within tumor, which was positively correlated with a survival benefit in mice bearing intracranial glioblastoma tumors. Consistent with our findings, there is increasing evidence indicating that p53 can regulate the cell‐mediated adaptive immune response to tumors and ultimately promote CTL‐induced cancer cell killing . Introduction of p53 into tumor cells has also been shown to enhance induction of apoptosis after exposure to CTL‐mediated cytotoxic insults, and p53 accumulation in tumor cells is an indispensable component in the GzmB‐induced apoptotic signaling pathway …”

“…Consistent with our findings, there is increasing evidence indicating that p53 can regulate the cellmediated adaptive immune response to tumors and ultimately promote CTL-induced cancer cell killing. [33][34][35][36] Introduction of p53 into tumor cells has also been shown to enhance induction of apoptosis after exposure to CTL-mediated cytotoxic insults, 35 and p53 accumulation in tumor cells is an indispensable component in the GzmB-induced apoptotic signaling pathway. 37 Generally speaking, cancer cells appear to create a tumor microenvironment that is relatively enriched in signals that polarize the TAMs toward the tumor-promoting M2 (alternatively activated) phenotype that can suppress antitumor immune responses.…”

PD-1, PD-L1, and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications

“…This association has been already described using cell lines and also in non-small cell lung cancer [29] but never for pancreatic cancer, and points out the intimate correlation of PD-L1 with tumor biology. This association may be also of importance in influencing the poorer prognosis of PD-L1 positive cases, since such tumors exhibit a more aggressive biological behavior [29,30].…”

Emerging Non-Canonical Functions and Regulation of p53

“…Accumulating evidence indicates that p53 and other tumor suppressors play important roles in immune response and inflammation either by directly or indirectly transactivating regulators involved in these processes [ 33 , 34 ]. Cui et al [ 35 ] summarize literatures showing the involvement of p53 in inflammation, tumor microenvironment (TME), and antitumor immunity.…”