Inhibition of PIM Kinase in Tumor-Associated Macrophages Suppresses Inflammasome Activation and Sensitizes Prostate Cancer to Immunotherapy
Immune checkpoint inhibitors (ICI) have changed the treatment paradigm for many cancers but have not shown benefit in prostate cancer. Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. In this study, we identify the proviral integration site for Moloney murine leukemia virus (PIM) kinases as regulators of inflammasome activation in tumor-associated macrophages (TAM). The analysis of clinical data from a cohort of patients with treatment-naïve, hormone-responsive prostate cancer revealed that tumors from patients with high PIM1/2/3 displayed an immunosuppressive tumor microenvironment 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 prostate cancer. 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 prostate cancer 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 prostate cancer.
Authors
- Elisabeth I. Heath (ORCID: https://orcid.org/0000-0003-1381-2713)
- Gregory C. Rogers (ORCID: https://orcid.org/0000-0003-1870-1713)
- Alejandro Recio‐Boiles (ORCID: https://orcid.org/0000-0002-5423-3112)
- Alex Farrell (ORCID: https://orcid.org/0000-0001-5702-3906)
- Rachel K. Toth (ORCID: https://orcid.org/0000-0001-8897-5045)
- Shailender S. Chauhan (ORCID: https://orcid.org/0000-0002-1975-2734)
- Chadi Nabhan (ORCID: https://orcid.org/0000-0002-4316-7826)
- Amber N. Clements (ORCID: https://orcid.org/0000-0002-6883-7558)
- Milan M. Radovich (ORCID: https://orcid.org/0000-0001-9667-156X)
- Sharon Wu (ORCID: https://orcid.org/0009-0004-3451-2247)
- Rana R. McKay (ORCID: https://orcid.org/0000-0002-0581-7963)
- Caitlyn E. Flores (ORCID: https://orcid.org/0000-0002-6714-3941)
- Hope Liou (ORCID: https://orcid.org/0000-0002-0466-5283)
- Noor Subah
- Andrea L. Casillas (ORCID: https://orcid.org/0000-0002-2059-3048)
- Travis J. Wheeler (ORCID: https://orcid.org/0000-0003-2004-1785)
- Justin E. Wilson (ORCID: https://orcid.org/0000-0002-2803-3280)
- Sara Centuori (ORCID: https://orcid.org/0000-0003-4857-847X)
- Joanne Xiu (ORCID: https://orcid.org/0000-0001-8744-5827)
- Anne E. Cress (ORCID: https://orcid.org/0000-0001-6194-0061)
- Noel A. Warfel (ORCID: https://orcid.org/0000-0001-6410-9011)
- Kai Sutterby
- Sachin Kumar Deshmukh
Institutions
- University of Arizona (US)
- University of San Diego (US)
- Wayne State University (US)
- Arizona Science Center (US)
- University of California San Diego (US)
- The Barbara Ann Karmanos Cancer Institute (US)
- Deerfield (United States) (US)
- Mayo Clinic in Arizona (US)
- Caris Life Sciences (United States) (US)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1158/2326-6066.cir-24-0591
- Citations
- 7
- Primary Topic
- Cancer Mechanisms and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 10.30