Amplifying TLR-MyD88 signals within tumor-specific T-cells enhances antitumor activity to suboptimal levels of weakly-immunogenic tumor-antigens

摘要

The efficacy of T-cell–based immunotherapy to treat cancer patients remains a challenge partly because of the weak activity toward subdominant tumor-antigens (TAg) and to tumors expressing suboptimal TAg levels. Recent reports indicate that Toll-like receptor (TLR) stimulation on T-cells can lower the activation threshold. In this study, we examined the anti-tumor activity and survival of TLR2-MyD88–stimulated CD8 T-cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2-stimulated pmel CD8 T-cells but not TLR2^−/−pmel or MyD88^−/−pmel T-cells responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88^−/− mice treated with TLR2 ligand and pmel T-cells, but not TLR2^−/−pmel or MyD88^−/−pmel T-cells, showed tumor regression of an established melanoma tumor. Over-expressing TLR2 in TA-specific T-cells eradicated tumors; four-times fewer cells were needed to generate anti-tumor responses. The enhanced anti-tumor activity of TLR2-MyD88–stimulated T-cells was associated with increased effector function but perhaps more importantly with improved survival of T-cells. Activating TLR-MyD88 signals in patient-derived T-cells also reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion and cytotoxicity. These data highlight a previously unappreciated role for activating TLR-MyD88 signals in tumor-reactive T-lymphocytes.