APR-246 increases tumor antigenicity independent of p53.

Abstract

We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activation of melanoma-specific CD8+ T cells and increased the efficacy of a tumor cell vaccine using MQ-treated cells even when the B16F10 cells lacked p53. We then designed a novel combination of APR-246 with the TLR-4 agonist, monophosphoryl lipid A, and a CD40 agonist to further enhance these immunogenic effects and demonstrated a significant antitumor response. We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.

• Authors: Judith Michels, Divya Venkatesh, Cailian Liu, Sadna Budhu, Hong Zhong, Mariam M George, Daniel Thach, Zhong-Ke Yao, Ouathek Ouerfelli, Hengrui Liu, Brent R Stockwell, Luis Felipe Campesato, Dmitriy Zamarin, Roberta Zappasodi, Jedd D Wolchok, Taha Merghoub
• Journal: Life science alliance (Life Sci Alliance) Vol. 7 Issue 1 (01 2024) ISSN: 2575-1077 [Electronic] United States
• PMID: 37891002 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 Michels et al.

Chemical References

• Tumor Suppressor Protein p53
• Antigens, Neoplasm

Topics

• Mice
• Animals
• CD8-Positive T-Lymphocytes
• Tumor Suppressor Protein p53 (genetics)
• Antigens, Neoplasm
• Melanoma