TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence

Accumulating evidence suggests the immunosuppressive microenvironments created by malignant tumors represent a major obstacle for effective anti-tumor immunity. A better understanding of the suppressive mechanisms mediated by tumor microenvironments and the development of strategies to reverse the immune suppression are major challenges for the success of tumor immunotherapy. Here, we report that human tumor cells can induce senescence in naïve/effector T cells, exhibiting potent suppressive function in vitro and in vivo. We further show that tumor-derived endogenous cyclic adenosine monophosphate (cAMP) is responsible for the induction of T-cell senescence. Importantly, activation of TLR8 signaling in tumor cells can block the induction and reverse the suppression of senescent naïve and tumor-specific T cells in vitro and in vivo, resulting in enhanced anti-tumor immunity. These studies identify a novel mechanism of human tumor-mediated immune suppression and provide a new strategy to reverse tumor immunosuppressive effects for tumor immunotherapy. Synopsis: This study identifies the induction of T-cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy. Tumor cells convert naïve/effector T cells into senescent T cells with potent suppressive function. Tumor-derived cAMP is responsible for the tumor cell-induced T-cell senescence. cAMP is directly transferred from tumor cells to targeted T cells through gap junctions inducing PKA-LCK inhibitory signaling and senescence in T cells. TLR8 signaling reverses tumor-induced T-cell senescence via down-regulation of cAMP in tumor cells. Activation of TLR8 signaling in tumor cells prevents tumor-specific T-cell senescence and enhances anti-tumor immunity. This study identifies the induction of T-cell senescence as a novel mechanism utilized by human tumor cells to induce immune suppression, and provides a new strategy using TLR8 ligands to reverse tumor immunosuppressive effects for tumor immunotherapy.