Barsoumian et al. find that prophylactic administration of a soluble, multimerizable fusion protein of 4-1BB ligand and streptavidin (SA-4-1BBL) alone prevented development of TC-1, LLC, and 3LL-huMUC1 tumors in mice in a dose- and timing-dependent manner. SA-4-1BBL expanded CD44+IFNγ+CD4+ T cells and IFNγ+ NK cells. Prophylactic anti-4-1BB agonistic antibody conferred neither effect. IFNγ blockade or depletion of CD4+ T cells or NK cells, but not CD8+ T cells and B cells, abrogated the protective effect of SA-4-1BBL. SA-4-1BBL treatment of mice with surgically resected TC-1 or 3LL-huMUC1 tumors prevented recurrence.
Contributed by Alex Najibi
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 IFNgamma-expressing, preexisting memory-like CD44(+)CD4(+) T cells and NK cells in naive mice as compared with the agonistic antibody. In vivo blockade of IFNgamma 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. SIGNIFICANCE: This study demonstrates the unique and unexpected immunomodulatory features of SA-4-1BBL that bridge innate and adaptive immune responses with both preventive and therapeutic efficacy against cancer.
Author Info: (1) Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
Author Info: (1) Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. (2) Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. (3) Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. (4) FasCure Therapeutics, LLC, Louisville, Kentucky. (5) Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. (6) Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. (7) Department of Surgery, University of Louisville, Louisville, Kentucky. (8) Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky. haval.shirwan@louisville.edu esma.yolcu@fascurether.com. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky. FasCure Therapeutics, LLC, Louisville, Kentucky. (9) Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky. haval.shirwan@louisville.edu esma.yolcu@fascurether.com. Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
