TLR2 signaling uniquely destabilizes tumor Tregs to promote cancer immunotherapy

A fundamental principle of immune responses is that innate immunity promotes adaptive immunity, but in the context of cancer immunity, the importance of innate receptor signaling is poorly defined. To study how Toll-like receptor (TLR) signaling contributes to cancer immunity, we used an attenuated strain of Listeria monocytogenes (Lm) that inhibits tumor growth in mice. We found that Lm stimulation of TLR2, but not TLR5 or TLR9, was essential for tumor control. As expected, TLR2 supported the priming of Lm-specific T cells in lymphoid tissues. However, TLR2 signaling in innate immune cells within tumors also destabilized Foxp3 expression in regulatory T cells (Tregs), a function that was not mediated by other TLRs. Reduced Treg function promoted tumor antigen cross-presentation by DC1s to enhance the functionality of recalled tumor-specific CD8+ T cells directly within tumors. These findings reveal a unique capacity for TLR2 signaling to diminish immunosuppression and promote cancer immunity.