Myeloid Pkcd Activation Inhibits Innate Immune Suppression And Promotes Antigen Cross-Presentation In Triple Negative Breast Cancer.

Abstract Immunotherapy has revolutionized cancer treatment showing unprecedented long-term antitumor responses. However, most patients do not respond to immunotherapy. Increasing preclinical and clinical evidence suggests that high tumor mutational burden does not always correlate with immunotherapy efficacy. Interestingly, cancers that have been associated with viruses imply that the pre-existing presentation of viral antigens may confer an increased response rate to immunotherapy. This suggests an important role of antigen presentation, particularly by the myeloid compartment in predicting immunotherapy efficacy. On the other hand, immunotherapy non-responders have high levels of circulating myeloid-derived suppressor cells (MDSCs)- an immunosuppressive innate cell population that suppresses T cells. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancers with poor responses to conventional therapies. TNBC patients harbor higher levels of MDSC populations compared to non-TNBC patients. Consequently, TNBC and other solid tumor patients who have high levels of circulating MDSCs respond poorly to immunotherapy. Hence, strategies that enhance antigen cross-presentation while altering MDSC's suppressive function represent a promising therapeutic approach to overcome immunotherapy resistance. Protein Kinase C (PKC) is a family of kinases composed of 11 isoforms that play a critical role in cell signaling. PKC delta (PKCδ) is the most abundant isoform in myeloid cells and plays an important role in dendritic cell (DC) function. To date, the role of PKCδ in myeloid cells in cancer is unknown. Using varied informatic approaches in patient databases, we found that BC patients with both high expression of PRKCD (PKCδ gene) and either high expression of CD8+ T cell or low expression of MDSC gene signatures in tumors had a significantly greater overall survival compared to other groups, suggesting support for activation of PKCδ. Novel preliminary data suggests that PKC agonism using FDA-approved PEP005 and prostratin reduced MDSC generation from BM progenitors specifically via activation of PKCδ isoform. PKC agonism induced MDSC differentiation to CD103+ DC-like cells both ex-vivo and in adoptive transfer experiment. Additionally, PEP005-treated MDSCs lost their suppressive capacity on CD8+ T cells in both in vitro and in vivo suppression assays. Importantly, PEP005 enhanced MDSC cross-priming capacity in both in vitro and in adoptive transfer experiments. Finally, treatment of TNBC-bearing C57BL/6J mice with PKC agonist PEP005 markedly reduced tumor burden by decreasing the frequencies of M-MDSCs in tumor, spleen, and bone marrow while increasing cDC1 frequencies in tumors. These findings propose PKCδ as a novel target in myeloid cells to tip the balance from immune suppression to effective antitumor immunity. Citation Format: Mehdi Chaib, Jeremiah Holt, Laura Sipe, Ajeeth Pingili, T.j. Hollingsworth, Deidre Daria, Neil Hayes, Liza Makowski. Myeloid PKCd activation inhibits innate immune suppression and promotes antigen cross-presentation in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 118.