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Introduction: Immune checkpoints have been the focus of intense research due to their critical roles in regulating immune responses. The CD137 is an immune checkpoint stimulator has pleiotropic immune functions along with its canonical role in driving CD8+ T cell responses. Using a novel form of its natural ligand (SA-4-1BBL) as a single agent, we recently showed its robust cancer immunoprevention efficacy against various transplantable tumor types in mice. In this study, we report its efficacy in a spontaneous tumor model and elucidate the mechanistic basis of prevention. Study design: Mice were treated subcutaneously with SA-4-1BBL protein twice, two weeks apart, and challenged with various tumor types 1-14 weeks later. Animals were monitored for tumor growth. The LSL-KrasG12D mice, as a model of spontaneous lung cancer, were intranasally infected with 2.5 × 107 PFUs of adenoviral-cre to induce cancer. Animals were treated with SA-4-1BBL twice, two weeks apart, pre or post-infection with adeno and euthanized at various times to collect the lung and lymphoid tissues for histopathology and flow cytometry. Results: Pretreatment with SA-4-1BBL was effective in preventing the growth of various transplantable tumors, B16-F10 melanoma, 3LL lung cancer, A20 lymphoma, 4T1 breast cancer, in different mouse strains. Treatment with SA-4-1BBL induced a window of protection against tumors that lasted over 14 weeks. SA-4-1BBL treatment significantly reduced the lung tumor burden in LSL-KrasG12D mice that was associated with increased absolute numbers of CD137+CD4+CD44hi T cells and CD137+NKG2D+NK cells expressing IFN-γ and TNF-α. A blocking antibody to NKG2D reversed the immunopreventive efficacy of SA-4-1BBL in the 3LL and B16-F10 tumor models, providing direct evidence for the role of this receptor in cancer immunoprevention. Gamma/delta T cells did not play a role in the cancer prevention efficacy of SA-4-1BBL as mice lacking these cells showed protection. Conclusions: These results demonstrate that SA-4-1BBL invokes an innate immune surveillance mechanism orchestrated by cross-communication between memory-like CD4+ T cells and NK cells with long-term protection against various tumor types. Funded in parts by NIH R41CA199956, T32HL134644, NCI R25CA134283, and Kentucky KSTC-184-512-16-237 awards. Citation Format: Haval Shirwan, Lalit Batra, Qingsheng Li, Mohammad T. Malik, Pradeep Shrestha, Nejat Egilmez, Esma S. Yolcu. A novel agonist of CD137 shows immunoprevention efficacy against various tumors by invoking an innate immune surveillance mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1422. |
