Pkc Agonism Restricts Immune Suppression And Promotes Antigen Cross-Presentation In Triple Negative Breast Cancer

Immunotherapy has revolutionized cancer treatment showing unprecedented long-term antitumor responses. However, most patients do not respond to immunotherapies due at least partly to immune suppression. 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 breast cancer patients. Consequently, TNBC and other solid tumor patients who have high levels of circulating MDSCs respond poorly to immunotherapy. On the other hand, cross-presenting dendritic cells (DCs) are essential to generate an antitumor immune response. Breast cancer patients who harbor higher numbers of these DCs have a better prognosis than patients with lower DC numbers. Several strategies aiming at achieving an effective combination with immunotherapy are under active investigation. The central dogma of these strategies consists of inducing T cells into “immunologically cold tumors” which are defined by having low neoantigen burden and a paucity of T cells and DCs. Hence, strategies that enhance cross-presenting DCs and T cell antitumor potential while altering MDSC’s suppressive function are likely to be effectively combined with immunotherapy for a maximum therapeutic benefit. Protein Kinase C (PKC) is a family of enzymes that play a critical role in cell signaling controlling the balance between survival and cell death. With the discovery in 1980s that PKC is a receptor for the tumor-promoting phorbol esters, the dogma that PKC is an oncoprotein was fueled. This led to more than three decades of failed clinical trials trying to inhibit PKC in cancer. Recent evidence suggests that PKC isozymes are generally inactivated in cancer and that most mutations affecting PKC isozymes are in fact loss of function mutations. This suggests that PKC is a tumor suppressor rather than an oncoprotein and that strategies in cancer treatment should focus on restoring PKC, rather than inhibiting it. To date, the role of PKC isozymes in antitumor immunity is unknown. Herein, our novel data suggest that PKC agonism using established agonists reduced MDSC generation from bone marrow (BM) progenitors specifically via activation of the PKC delta (PKCδ) isoform. PKC agonism induced MDSC differentiation to cross-presenting CD103+ DCs both ex-vivo and in vivo. Additionally, PKC agonist-treated purified MDSCs lost their suppressive capacity on CD8+ T cells in both in vitro and in vivo suppression assays. In contrast, PKC agonism significantly increased the generation of cross-presenting DCs (cDC1) from BM progenitors. 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 tumor and spleen. These findings propose PKC as a common pathway in myeloid cells to tip the balance from immune suppression to effective antitumor immunity. Citation Format: Mehdi Chaib, Jeremiah Holt, Laura Sipe, Ajeeth Pingili, Deidre Daria, Liza Makowski. Pkc agonism restricts immune suppression and promotes antigen cross-presentation in triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-46.