| First Author | Ghosh A | Year | 2022 |
| Journal | J Clin Invest | Volume | 132 |
| Issue | 18 | PubMed ID | 36106631 |
| Mgi Jnum | J:336978 | Mgi Id | MGI:7341328 |
| Doi | 10.1172/JCI148141 | Citation | Ghosh A, et al. (2022) Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade. J Clin Invest 132(18):e148141 |
| abstractText | 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. |
