APR-246 increases tumor antigenicity independent of p53

• Published in: Life science alliance 2024-01, Vol.7 (1), p.e202301999
• Main Authors: Michels, Judith, Venkatesh, Divya, Liu, Cailian, Budhu, Sadna, Zhong, Hong, George, Mariam M, Thach, Daniel, Yao, Zhong-Ke, Ouerfelli, Ouathek, Liu, Hengrui, Stockwell, Brent R, Campesato, Luis Felipe, Zamarin, Dmitriy, Zappasodi, Roberta, Wolchok, Jedd D, Merghoub, Taha
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Melanoma; Mice; Tumor Suppressor Protein p53 - genetics
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202301999

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.