Stimulation of Natural Killer Cell-Mediated Tumor Immunity by an IL15/TGF?-Neutralizing Fusion Protein.

ABSTRACT: The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGF?. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell-stimulatory cytokine IL15, the sushi domain of IL15R? and a TGF? ligand trap, can overcome immunosuppressive TGF? to effectively stimulate the proliferation and activation of natural killer (NK) and CD8+ T cells with potent antitumor properties. FIST15-treated NK and CD8+ T cells produced more IFN? and TNF? compared with treatment with IL15 and a commercially available TGF? receptor-Fc fusion protein (sT?RII) in the presence of TGF?. Murine B16 melanoma cells, which overproduce TGF?, were lysed by FIST15-treated NK cells in vitro at doses approximately 10-fold lower than NK cells treated with IL15 and sT?RII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Finally, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared with tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGF? in the tumor microenvironment while empowering tumor immunity. Cancer Res; 76(19); 5683-95. ©2016 AACR.

SUBMITTER: Ng S 

PROVIDER: S-EPMC5050108 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature