A novel form of 4-1BBL prevents cancer development via non-specific activation of CD4+ T and Natural Killer cells

Costimulation through 4–1BB (CD137) receptor generates robust CD8 + T effector and memory responses. The only known ligand, 4–1BBL, is a trimeric transmembrane protein that has no costimulatory activity as a soluble molecule. Thus, agonistic antibodies to the receptor have been used for cancer immunotherapy in preclinical models and are currently being evaluated in the clinic. Here we report that treatment with an oligomeric form of the ligand, SA-4–1BBL, as a single agent is able to protect mice against subsequent tumor challenge irrespective of the tumor type. Protection was long-lasting (> 8 weeks) and a bona fide property of SA-4–1BBL, as treatment with an agonistic antibody to the 4–1BB receptor was ineffective in generating immune protection against tumor challenge. Mechanistically, SA-4–1BBL significantly expanded IFN-γ-expressing, pre-existing memory-like CD44 + CD4 + T cells and NK cells in naïve mice as compared to the agonistic antibody. In vivo blockade of IFN-γ or depletion of CD4 + T or NK cells, but not CD8 + T or B cells, abrogated the immunopreventive effects of SA-4–1BBL against cancer. SA-4–1BBL as a single agent also exhibited robust efficacy in controlling postsurgical recurrences. This work highlights unexpected features of SA-4–1BBL as a novel immunomodulator with implications for cancer immunoprevention and therapy.