Amplifying TLR-MyD88 signals within tumor-specific T-cells enhances antitumor activity to low concentrations of subdominant tumor-antigens (101.35)

Abstract

Abstract There is a dire need to understand the cellular signals that can potentiate T-cell responses to weakly immunogenic tumor antigens (TAg) and to tumors expressing suboptimal levels of these antigens. We examined the anti-tumor activity and survival of TLR2-MyD88-stimulated tumor-specific CD8 T-cells derived from melanoma patients and TAg-specific T-cell receptor transgenic pmel mice. TLR2 engagement on pmel CD8 T-cells, but not on TLR2-/-pmel or MyD88-/-pmel T-cells, reduced the activation threshold to a subdominant TAg, resulting in increased production of effector molecules and cytotoxicity. Wild-type or MyD88-/- mice treated with pmel T-cells and TLR2 ligand, but not TLR2-/-pmel or MyD88-/-pmel T-cells, showed significant tumor regression of an established melanoma tumor. Over-expressing TLR2 in pmel T-cells eradicated established tumors and four-times fewer cells were needed to generate anti-tumor responses. The enhanced anti-tumor activity was associated with improved survival and increased effector function of TLR2-MyD88-stimulated T-cells. Activating TLR-MyD88 signals in patient-derived T-cells reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion and cytotoxicity. These data highlight the physiological importance of activating TLR-MyD88 signals within tumor-reactive T-lymphocytes for enhancing their longevity and augmenting effector function against suboptimal levels of weakly-immunogenic antigens.