{
  "abstract": "Background While immune checkpoint blockade and costimulatory agonists have shown clinical promise, their efficacy is often limited by insufficient infiltration of effector immune cells into the tumor microenvironment (TME). Chemerin ( RARRES2), an endogenous leukocyte chemoattractant, recruits immune cells via its receptor CMKLR1, expressed on NK cells, CD8+ T-cell subsets, dendritic cells (DCs), and macrophages.1–4 Notably, RARRES2 expression is frequently downregulated in various cancers, including prostate cancer. Here, we investigate the effect of chemerin on immune cell recruitment/activation and tumor suppression in a syngeneic prostate cancer model.Methods Male C57BL/6 mice were subcutaneously injected with TRAMP-C1 prostate cancer cells overexpressing RARRES2, vector control (VC), or a 1:1 mixture of both. Tumor growth was monitored, and tumor-infiltrating leukocytes (TILs) were analyzed by flow cytometry. Where indicated, mice received intraperitoneal injections of anti-PD-1 or isotype control antibody. Functional roles of immune subsets were assessed by in vivo depletion studies.Results RARRES2 overexpression did not affect TRAMP-C1 tumor cell growth in vitro but significantly suppressed tumor growth in vivo. This was associated with increased infiltration of NK (CD3–CD19–NK1.1+) and CD8+ T cells (CD3+CD8+) into the TME. Depletion studies confirmed that both NK and CD8+ T cells, but not CD4+ T cells, were essential for chemerin-mediated tumor suppression. Chemerin-expressing tumors also induced systemic immune alterations, including elevated splenic NK and CD8+ T cells and reduced granulocytic myeloid-derived suppressor cells (G-MDSCs). Anti-PD-1 monotherapy was ineffective in control tumors, but significantly enhanced tumor regression and complete response rates in chemerin-expressing tumors. Chemerin overexpression also promoted the frequency and activation of cross-presenting XCR1+ conventional dendritic cells (cDC1s) in the TME, characterized by upregulation of MHC-I, CD80, and CD86. Ex vivo, chemerin treatment of DCs enhanced antigen presentation and CD8+ T cell activation in an antigen-specific manner.Conclusions This is first study to demonstrate that chemerin expression within the prostate TME suppresses tumor growth by promoting recruitment and activation of effector NK and CD8 + T cells and enhancing antigen presentation via cDC1s (figure 1). Chemerin expression enhances the efficacy of immune checkpoint blockade in otherwise unresponsive tumors. These findings support the development of chemerin-based immunotherapies to improve responses in prostate cancer, particularly in tumors otherwise resistant to immunotherapy.References Ballet R, et al. Chemerin triggers migration of a CD8 T cell subset with natural killer cell functions. Mol Ther. 2023;31:2887–2900.Saeed MA, et al. High-dimensional analyses reveal IL15 enhances activation of sipuleucel-T lymphocyte subsets and reverses immunoresistance. Cancer Immunology Research. 2024;12:559–574.Rennier K, Shin WJ, Krug E, Virdi G, Pachynski RK. Chemerin reactivates PTEN and suppresses PD-L1 in tumor cells via modulation of a novel CMKLR1-mediated signaling cascade. Clinical Cancer Research. 2020;26:5019–5035.Shin WJ, Pachynski RK. Chemerin modulation of tumor growth: potential clinical applications in cancer. Discovery Medicine 2018;26:31–37.Ethics Approval All animal studies were performed in accordance with Washington University and NIH Institutional Animal Care and Use Committee guidelines under an approved protocol (No. 23–0247).Abstract 904 Figure 1Mechanism of action of chemerin in TME",
  "authors": [
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Muhammad Azeem Saeed"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Kevin Kim"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Sandeep S Panikar"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Kavita Rawat"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Sara McCoy"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Nehla Banu"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Daniel Thorek"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, Saint Louis, MO, USA"
      ],
      "name": "Russell K Pachynski"
    }
  ],
  "title": "904 Chemerin suppresses prostate tumor growth by enhancing antigen presentation and effector NK and CD8+ T cell recruitment to the tumor microenvironment",
  "uid": "36a18d97-0746-57b3-ac0d-0b373c3c7124"
}