Inhibition of PIM kinase in tumor-associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy.

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Tác giả: Andrea L Casillas, Sara Centuori, Shailender S Chauhan, Amber N Clements, Anne E Cress, Sachin Kumar Deshmukh, Alex Farrell, Caitlyn E Flores, Elisabeth I Heath, Hope Liou, Rana R McKay, Chadi Nabhan, Milan Radovich, Alejandro Recio-Boiles, Gregory C Rogers, Noor Subah, Kai Sutterby, Rachel K Toth, Noel A Warfel, Travis J Wheeler, Justin E Wilson, Sharon Wu, Joanne Xiu

Ngôn ngữ: eng

Ký hiệu phân loại: 809.008 History and description with respect to kinds of persons

Thông tin xuất bản: United States : Cancer immunology research , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 711323

Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for many cancers but have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as regulators of inflammasome activation in tumor-associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone-responsive PCa patients revealed that tumors from patients with high PIM1/2/3 displayed an immunosuppressive TME characterized by high inflammation and a high density of repressive immune cells, most notably TAMs. Macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of PCa. Transcriptional analyses indicated that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized PCa tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Our data implicate macrophage PIM as a driver of inflammation that limits ICI potency and provide preclinical evidence that PIM inhibitors are an effective strategy to improve the ICI efficacy in PCa.
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