The role of p53 in anti-tumor immunity and response to immunotherapy

Frontiers in Molecular Biosciences

Molecular Biosciences

Xiaobing Tian¹  Andrew George¹  Shengliang Zhang¹  Arielle De La Cruz¹  Taylor E. Arnoff¹  Lindsey Carlsen²  Wafik S. El-Deiry³ 

[1] Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States;Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States;Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States;Legorreta Cancer Center, Brown University, Providence, RI, United States;Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States;Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States;Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States;Legorreta Cancer Center, Brown University, Providence, RI, United States;Pathobiology Graduate Program, Warren Alpert Medical School, Brown University, Providence, RI, United States;Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States;Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States;Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States;Legorreta Cancer Center, Brown University, Providence, RI, United States;Pathobiology Graduate Program, Warren Alpert Medical School, Brown University, Providence, RI, United States;Hematology-Oncology Division, Department of Medicine, Lifespan Health System and Warren Alpert Medical School, Brown University, Providence, RI, United States;

关键词: p53;    immunotherapy;    anti-cancer immunity;    tumor microenvironment;    DNA damage;   

DOI  :  10.3389/fmolb.2023.1148389

 received in 2023-01-20, accepted in 2023-07-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

p53 is a transcription factor that regulates the expression of genes involved in tumor suppression. p53 mutations mediate tumorigenesis and occur in approximately 50% of human cancers. p53 regulates hundreds of target genes that induce various cell fates including apoptosis, cell cycle arrest, and DNA damage repair. p53 also plays an important role in anti-tumor immunity by regulating TRAIL, DR5, TLRs, Fas, PKR, ULBP1/2, and CCL2; T-cell inhibitory ligand PD-L1; pro-inflammatory cytokines; immune cell activation state; and antigen presentation. Genetic alteration of p53 can contribute to immune evasion by influencing immune cell recruitment to the tumor, cytokine secretion in the TME, and inflammatory signaling pathways. In some contexts, p53 mutations increase neoantigen load which improves response to immune checkpoint inhibition. Therapeutic restoration of mutated p53 can restore anti-cancer immune cell infiltration and ameliorate pro-tumor signaling to induce tumor regression. Indeed, there is clinical evidence to suggest that restoring p53 can induce an anti-cancer immune response in immunologically cold tumors. Clinical trials investigating the combination of p53-restoring compounds or p53-based vaccines with immunotherapy have demonstrated anti-tumor immune activation and tumor regression with heterogeneity across cancer type. In this Review, we discuss the impact of wild-type and mutant p53 on the anti-tumor immune response, outline clinical progress as far as activating p53 to induce an immune response across a variety of cancer types, and highlight open questions limiting effective clinical translation.

【 授权许可】

Unknown   
Copyright © 2023 Carlsen, Zhang, Tian, De La Cruz, George, Arnoff and El-Deiry.