Abstract LB390: Phagocytes play a critical role in the efficacy of a novel agonist of CD137 in preventing various tumor types

Abstract Introduction: A novel CD137 agonist, SA-4-1BBL, as a single agent is effective in training the immune system to prevent cancer development in preclinical models. The cancer immunoprevention efficacy of SA-4-1BBL is tumor-type independent, long-lasting (>14 weeks), and requires immune cells expressing CD4 or NK1.1 molecules but not CD8+ T cells, implicating innate immune surveillance. Since NKT cells express both CD4 and NK1.1, we herein investigated the role of these cells, phagocytes, and neutrophils in cancer immunoprevention efficacy of SA-4-1BBL. Study Design: Wild-type, CD1d-/-KO lacking all NKT cells, and Jα18-/-KO lacking invariant NKT cells were treated subcutaneously with SA-4-1BBL twice two weeks apart. Mice were challenged two weeks later subcutaneously with syngeneic cervical cancer (TC-1) or Lewis lung carcinoma (LLC) and monitored for tumor development. To deplete phagocytes, clodronate-loaded liposomes were administrated 2 days prior to each SA-4-1BBL treatment (priming) or 2 days before the tumor challenge (effector). Neutrophils were depleted using anti-Ly6G Ab 2 days before each SA-4-1BBL treatment. Mice treated with PBS-loaded liposome or saline served as controls. Draining lymph nodes from tumor-free mice at 60 days post-challenge were used for deep immunophenotyping to assess long-lasting immune correlates of cancer immunoprevention. Results: Pretreatment with SA-4-1BBL prevented tumor growth in both TC-1 and LLC challenged mice (> 70%). Deep immunophenotyping demonstrated that SA-4-1BBL significantly increased absolute numbers of CD4+ T, NK, NKT cells, macrophages, and neutrophils as compared to naïve mice. SA-4-1BBL was effective in preventing tumor growth in mice lacking invariant NKT (Jα18-/-KO, 100%), all NKT (CD1d-/-KO, >60%) cells, or mice depleted for neutrophils (>70%). Importantly, clodronate-mediated phagocyte depletion significantly reduced the tumor immunoprevention efficacy to 20% at both priming and effector phases, whereas treatment with PBS-loaded liposome as control showed a similar immunoprevention efficacy (∼68%) as SA-4-1BBL-treated experimental group. Conclusion: These studies demonstrated that phagocytes (monocytes, macrophages, and dendritic cells) but not NKT or neutrophils play critical roles in cancer immunoprevention efficacy of SA-4-1BBL. Ongoing studies using mice lacking monocyte/macrophage or DCs will elucidate the contribution of each cell population to the immunoprevention efficacy of SA-4-1BBL. Elucidation of mechanistic underlying of cancer immunoprevention will facilitate clinical translation of this approach as a potential universal platform to combat cancer. Acknowledgment: Supported in part by Paula and Rodger Riney Foundation and NCI (1UG3CA290305). Citation Format: Feyza Nur Arguc, Mohammad Tarique, Vahap Ulker, Esma S. Yolcu, Haval Shirwan. Phagocytes play a critical role in the efficacy of a novel agonist of CD137 in preventing various tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB390.