Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade Journal Article
| Authors: | Ghosh, A.; Michels, J.; Mezzadra, R.; Venkatesh, D.; Dong, L.; Gomez, R.; Samaan, F.; Ho, Y. J.; Campesato, L. F.; Mangarin, L.; Fak, J.; Suek, N.; Holland, A.; Liu, C.; Abu-Akeel, M.; Bykov, Y.; Zhong, H.; Fitzgerald, K.; Budhu, S.; Chow, A.; Zappasodi, R.; Panageas, K. S.; de Henau, O.; Ruscetti, M.; Lowe, S. W.; Merghoub, T.; Wolchok, J. D. |
| Article Title: | Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade |
| 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. |
| Keywords: | genetics; mouse; animal; animals; mice; cancer immunotherapy; oncology; protein p53; immunotherapy; tumor suppressor protein p53; p53; therapeutics; pharmacology; tumor microenvironment; tumor-associated macrophages; quinuclidines; quinuclidine derivative; immune checkpoint inhibitors; eprenetapopt |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 132 |
| Issue: | 18 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2022-09-15 |
| Start Page: | e148141 |
| Language: | English |
| DOI: | 10.1172/jci148141 |
| PUBMED: | 36106631 |
| PROVIDER: | scopus |
| PMCID: | PMC9479603 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2022 -- Source: Scopus |
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