The potential for p53 reactivators to increase the sensitivity of aggressive gynecologic cancers to immunotherapy 3272

Abstract Description The most aggressive ovarian and endometrial cancers frequently harbor a mutation in the tumor suppressor p53, which plays a critical role in tumorigenesis and immune evasion. In this study, we evaluated the effects of two novel p53 reactivators, HO-3867 and AKT-100, which bind p53 and re-establish wild type (WT) p53 transcriptional effects. Both agents significantly inhibited growth of ovarian and endometrial cancer cell lines containing various mutations in TP53. Using RNA-sequencing, we found immunomodulatory pathways to be affected after p53 reactivator treatment, especially the upregulation of antigen processing and presentation genes. Genes encoding for MHC I and II, heat shock proteins, cytokines and chemokines, and the immune-proteasome were up-regulated in response to the agents. Immunotherapy is an important new FDA approved treatment approach that is now standard of care for endometrial cancers. However, ovarian cancers have shown a lack of response to PD-1/PD-L1 inhibitors and it’s possible that mutant p53 proteins contribute to the inhibition of CD8+ T cell tumor response. Thus, the reactivation of WT p53 functionality in ovarian cancers has the potential to sensitize tumors to immunotherapy via targeting PD-L1, found to be upregulated in these studies. Our results support the therapeutic potential of p53 reactivators to enhance anti-tumor immunity and highlight the need for exploration of p53 mutations as modulators of immune function in gynecologic cancers. Funding Sources Supported by the following grants: 5R01CA99908-21 (KL), CDMRP CA210610 (KL), CDMRP CA2220729 (KL), P50CA264793 (KL), The University of New Mexico Comprehensive Cancer Center (UNMCCC) P30CA118100, with support from the UNMCCC Biostatistics and Animal Models Shared Resources. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)