Costimulatory Effects of TLR1-TLR2 signaling in CD8+ T Cells

Abstract

The future of T cell-based immunotherapy for cancer currently faces two predominant challenges; the development of an effective strategy to enhance the effector function of anti-tumor T cells and a method to overcome the barrage of suppressive mechanisms mediated by suppressive cells (such as MDSCs) within the immunosuppressive tumor microenvironment. The activation of the TLR-MyD88 signaling pathway in CD8+ T cells augments their proliferation, cytokine production and anti-tumor potency in vivo. Our studies explored the molecular pathways activated by TLR stimulation with a focus on mechanisms that enhance anti-tumor properties. Transcriptomic analysis of TLR-stimulated T cells revealed an enhanced expression of several TNFRSF members including 4-1BB. Blocking or deleting 4-1BB diminished the effects of TLR1-TLR2 stimulation. Furthermore, combined administration of a TLR1-TLR2 ligand and an agonistic 4-1BB antibody augmented T cell proliferation and cytokine production more than either therapeutic agent alone. This combination therapy strategy also induced significant tumor regression in mice bearing an established B16 melanoma. We also tested the ability of TLR1-TLR2-stimulated T cells to withstand MDSC-mediated suppression. TLR1-TLR2-treated T cells exhibited greater proliferation and cytokine production than non-treated T cells in the presence of tumor-derived MDSCs. This phenomenon was recapitulated in T cells transduced to express a synthetic CD8α:MyD88 coreceptor, which activates the MyD88 pathway specifically upon TCR engagement. The results presented in this study emphasize the strength and potential clinical use of activating the TLR signaling pathway in the development of immunotherapy strategies against cancer.