Molecular control of human regulatory T cell suppression for tumor immunotherapy (P2106)

Immunotherapy is a promising approach for treating patients with malignant tumor, but immunosuppressive microenvironments induced by regulatory T cells (Tregs) present a major barrier to successful anti-tumor immunotherapy. A better understanding of the suppressive mechanisms utilized by Tregs is essential for the development of novel strategies to treat human cancer. Here we report that human Tregs can induce senescence in responder naïve and effector T cells in vitro and in vivo. Senescent responder T cells induced by human Tregs changed their phenotypes and cytokine profiles, and possessed potent suppressive function. Furthermore, Treg-mediated molecular control of senescence in responder T cells was associated with selective modulation of p38 and ERK1/2 signaling and cell cycle regulatory molecules p16, p21 and p53. We further revealed that human Treg-induced senescence and suppressor function could be blocked by TLR8 signaling and/or by specific ERK1/2 and p38 inhibition in vitro and in vivo in animal models. Our studies identify a novel mechanism of human Treg cell suppression that induces targeted responder T cell senescence, and provide new insights relevant for the development of strategies capable of preventing and/or reversing Treg-induced immune suppression for tumor immunotherapy.