Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade

Ghosh, Arnab, Michels, Judith, Mezzadra, Riccardo, Venkatesh, Divya, Dong, Lauren, Gomez, Ricardo, Samaan, Fadi, Ho, Yu-Jui, Campesato, Luis Felipe, Mangarin, Levi, Fak, John, Suek, Nathan, Holland, Aliya, Liu, Cailian, Abu-Akeel, Mohsen, Bykov, Yonina, Zhong, Hong, Fitzgerald, Kelly, Budhu, Sadna, Chow, Andrew, Zappasodi, Roberta, Panageas, Katherine S, de Henau, Olivier, Ruscetti, Marcus, Lowe, Scott W, Merghoub, Taha, Wolchok, Jedd D (September 2022) Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade. Journal of Clinical Investigation, 132 (18). e148141. ISSN 0021-9738

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Abstract

In addition to playing a major role in tumor cell biology, p53 generates a microenvironment that promotes antitumor immune surveillance via tumor-associated macrophages. We examined whether increasing p53 signaling in the tumor microenvironment influences antitumor T cell immunity. Our findings indicate that increased p53 signaling induced either pharmacologically with APR-246 (eprenetapopt) or in p53-overexpressing transgenic mice can disinhibit antitumor T cell immunity and augment the efficacy of immune checkpoint blockade. We demonstrated that increased p53 expression in tumor-associated macrophages induces canonical p53-associated functions such as senescence and activation of a p53-dependent senescence-associated secretory phenotype. This was linked with decreased expression of proteins associated with M2 polarization by tumor-associated macrophages. Our preclinical data led to the development of a clinical trial in patients with solid tumors combining APR-246 with pembrolizumab. Biospecimens from select patients participating in this ongoing trial showed that there was a suppression of M2-polarized myeloid cells and increase in T cell proliferation with therapy in those who responded to the therapy. Our findings, based on both genetic and a small molecule-based pharmacological approach, suggest that increasing p53 expression in tumor-associated macrophages reprograms the tumor microenvironment to augment the response to immune checkpoint blockade.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > immunity organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent
CSHL Authors:	Lowe, Scott W.
Communities:	CSHL labs > Lowe lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	15 September 2022
Date Deposited:	13 Oct 2023 17:38
Last Modified:	11 Jan 2024 20:19
PMCID:	PMC9479603
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41259

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