Abstract B026: PIM kinases regulates tumor associated macrophage survival and inflammatory signaling

Abstract Prostate tumors are highly infiltrated by immunosuppressive tumor associated macrophages (TAMs). TAMs secrete various factors that promote tumor progression and suppress antitumor immunity, making them a promising therapeutic target. PIM kinases are serine/threonine kinases that are overexpressed in several tumor types including prostate cancer. PIM regulates many signaling pathways that promote cell proliferation and cell survival. However, the role of PIM in macrophages is not well understood. Macrophages express NLRP3, a cytosolic innate immune sensor, that forms a complex with ASC and caspase-1 termed the inflammasome. Activation of the inflammasome leads to release of proinflammatory cytokines including IL-1β and induces pyroptotic cell death. We hypothesize that PIM promotes macrophage survival by suppressing inflammasome activation. To test our hypothesis, we treated mouse bone marrow derived macrophages (BMDMs) with PIM447, a pan-PIM kinase inhibitor, and activated the inflammasome via lipopolysaccharide (LPS) and ATP stimulation. Preliminary data demonstrates that PIM inhibition in BMDMs promotes increased inflammasome activation as indicated by increased cleaved caspase-1 and increased IL-1β secretion. Recent studies have demonstrated that PIM kinases promote immune evasion through the modulation of both tumor cells and immune cells within the tumor microenvironment. We hypothesize that PIM kinase promotes TAM survival leading to increased immunosuppression and immunotherapy resistance in prostate cancer. We treated immunocompetent mice injected with MyC-Cap prostate cancer cells with PIM447. PIM inhibition decreased tumor growth and decreased the presence of tumor associated macrophages. In summary, the results of these studies suggest that PIM plays an important role in regulating macrophage survival and inflammatory signaling. Furthermore, PIM may be a potential target to enhance the efficacy of immunotherapies for the treatment of prostate cancer. Citation Format: Amber N. Clements, Noel A. Warfel. PIM kinases regulates tumor associated macrophage survival and inflammatory signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B026.