A novel agonist of CD137 immune checkpoint stimulator serves as a cancer immunoprevention agent with efficacy against various tumor types

Abstract

Abstract Background CD137 immune checkpoint stimulator plays an important role in T cell responses and has been targeted for cancer immunotherapy using agonistic Abs with shown toxicity. We herein report that a novel oligomeric form of the CD137 ligand, SA-4-1BBL, as a single agent has robust cancer immunoprevention efficacy against various tumors in mice without detectable toxicity, whereas an agonistic Ab to CD137 did not protect mice against tumor challenge. Study Design Mice (C57BL/6 or BALB/c) were pretreated s.c. with SA-4-1BBL protein or an agonistic Ab (3H3) to CD137 and subsequently challenged s.c. at various times (0 to 12 weeks) with different tumor cell lines. SA-4- 1BBL-treated mice without tumor challenge were euthanized 7 days later to harvest lymphoid tissues for immunophenotyping. Results Pretreatment with SA-4-1BBL protected mice against 4 different tumor types; 3LL lung, TC-1 cervical, B16-F10 melanoma, and A20 lymphoma. The conferred protection against tumors was dose-dependent and evolved within two weeks of SA-4-1BBL pretreatment and lasted for > 8 weeks. In marked contrast, pretreatment with the agonistic Ab had no impact on the tumor growth. CD4+CD44+CD137+ T cells and NK cells producing IFN- γ were expanded by SA-4-1BBL. Depletion of CD4+ T and NK cells or blockade of IFN-γ totally abrogated the protective effect. Depletion of CD8+ T or B cells had no significant impact on tumor growth. Importantly, SA-4- 1BBL as a single agent also prevented post-surgical tumor recurrences. Conclusion This study demonstrates that SA-4-1BBL is a novel CD137 agonist with desired features for cancer immunoprevention and immunotherapy.