Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4 <sup>+</sup> T cell response
Aleksey Chudnovskiy, Tiago B. R. Castro, Sandra Nakandakari-Higa, Ang Cui, Chia‐Hao Lin, Moshe Sade-Feldman, Brooke K. Phillips, Juhee Pae, Luka Mesin, Juliana Bortolatto, Lawrence D. Schweitzer, Giulia Pasqual, Li‐Fan Lu, Nir Hacohen, Gabriel D. Victora
Abstract
Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)–based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4 + T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4 + and CD8 + tumor–specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.