Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+ T cell response.

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. Editor's summary: Dendritic cells (DCs) are critical for generating antitumor T cell responses, including after immune checkpoint blockade, but the features of specific DCs involved in this process are not well defined. Using LIPSTIC proximity–based labeling in combination with single-cell transcriptomics, Chudnovskiy et al. characterized individual DCs presenting tumor-derived antigen in a mouse model of melanoma. In tumor-draining lymph nodes, antigen-presenting DCs constituted less than 15% of all DCs and adopted a hyperactivated phenotype characterized by IL-27 production. In tumors, T cell–interacting DCs adopted a similar, albeit less mature, transcriptional state. Interactions between DCs and T cells were enhanced by anti–CTLA-4 immune checkpoint blockade, highlighting the importance of these contacts in driving antitumor immune responses. —Claire Olingy [ABSTRACT FROM AUTHOR]