Novel checkpoint receptors on dendritic cells license the cytotoxic activity of tumor-infiltrating T cells

Dendritic cells (DC), are widely appreciated for their prominent capacity to stimulate anti-tumor T cells. Nevertheless, attempts to harness DC vaccination as a therapeutic strategy did not lead to eradication of established solid tumors. Thus, a better understanding of DC mechanisms is an urgent challenge to develop improved immunotherapy. We have recently provided new insights to the limited clinical benefit of DC vaccines by demonstrating that T cells must obtain two signals, by different DC subsets in order to elicit their cytotoxic activity: MHC-dependant signal in the tumor-draining lymph nodes (DLN) by classical DC, and an additional one, which is MHC-independent, in the tumor sites by activated monocyte-derived DC (MoDC). We further demonstrated that vaccinations with both classical and MoDC pulsed with tumor antigens are not sufficient to induce tumor regression in mice with established tumors. Our findings indicated that signals provided by activated MoDC are requisite for eliciting in situ the cytotoxic activity of antigen-experienced CD8+ T cells. However, the mechanism of this novel interaction pathway between DC and T cells is unknown.

Overall, this study provides novel insights into the spatial organization of DC subsets across the organism in cancer and into the unique signals that each subset provides to T cells. The results from this work are also expected to revisit the signaling cascade required to fully activate T cells and to suggest a therapeutic framework to increase the potency of CD8+ T cell-based therapies in “cold tumors” and in non-responding individuals.