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eSymposia | Myeloid Cells and Innate Immunity in Solid Tumors


PKC Delta Activation Restricts Innate Immune Suppression and Promotes antigen Presentation in Triple Negative Breast Cancer


Sep 21, 2020 12:00am ‐ Sep 21, 2020 12:00am

Description

PKC Delta Activation Restricts Innate Immune Suppression and Promotes antigen Presentation in Triple Negative Breast Cancer 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. 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 (cDC1) 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 kinases composed of 11 isoforms that play a critical role in cell signaling. PKC delta (PKCd) is the most abundant isoform in myeloid cells and plays an important role in dendritic cell (DC) function. To date, the role of PKCd 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 (PKCd 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 PKCd. Novel preliminary data suggests that PKC agonism using FDA-approved PEP005 and prostratin reduced MDSC generation from BM progenitors specifically via activation of PKCd isoform. PKC agonism induced MDSC differentiation to Ly6C+ CD103+ DCs 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. 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 PKCd as a novel target in myeloid cells to tip the balance from immune suppression to effective antitumor immunity.

Speaker(s):

  • Mehdi Chaib, M.S., University of Tennessee Health Science Center

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