PKC agonism restricts innate immune suppression and promotes antigen cross-presentation in Triple Negative Breast Cancer

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SUMMARY Immune checkpoint blockade (ICB) has revolutionized cancer therapy showing unprecedented long-term antitumor responses. However, most patients do not respond to ICB therapies due at least partly to immunosuppression. Immunotherapy non-responders have high levels of circulating myeloid-derived suppressor cells (MDSCs)- an immunosuppressive innate cell population that suppresses both innate and adaptive immunity. 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 ICB. Hence, strategies that reduce MDSC’s suppressive function while promoting cross-priming of CD8+ T cells are likely to be effectively combined with ICB for a maximum therapeutic benefit. Protein Kinase C (PKC) is a family of kinases composed of 11 isoforms that play a critical role in cell signaling. PKC delta (PKC) is the most abundant isoform in myeloid cells and plays an important role in dendritic cell (DC) function. To date, the role of PKC in myeloid cells in cancer is unknown. Using varied informatic approaches in patient databases, I found that BC patients with both high expression of PRKCD 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 PKC. Novel preliminary data suggests that PKC agonism using FDA-approved PEP005 and prostratin reduced MDSC generation from bone marrow progenitors specifically via activation of PKC isoform. PKC agonism induced MDSC differentiation to CD103+ DC-like cells both ex-vivo and in vivo. Additionally, PEP005-treated MDSCs lost their suppressive capacity on CD8+ T cells in both in vitro and in vivo pilot suppression assays and efficiently cross-primed OT-I CD8+ T cells. Mechanistic studies reveal transcription factor IRF5 as a potential target of PKC-to be explored in this proposal. Based on rigorously generated pilot data, I hypothesize that PKC agonism combined with agonistic CD40 mAb will sensitize TNBC tumors to ICB through induced differentiation of MDSCs to DC-like cells via activation of PKC and its downstream target IRF5. CD40 is mainly expressed by myeloid cells and its activation has been shown to effectively activate antigen-presenting cells. Aim 1 & 2 will determine if PKC activation controls MDSC and DC phenotype and function and will determine to what extent pharmacologic activation of PKC in combination with agonistic CD40 mAb improves anti-PD-L1 therapy in TNBC mouse models. The proposed training will prepare me for my long-term goal of becoming a tumor immunologist with a research objective to develop novel immunomodulatory therapeutic approaches against solid tumors as an independent investigator.