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

Abstract

Dendritic cells (DCs) are uniquely capable of transporting tumoral antigens to tumor-draining lymph nodes (tdLNs), where they initiate antitumor immunity and mediate checkpoint blockade immunotherapy. Despite recent advances, the full phenotype of the DCs involved in these processes has been difficult to establish. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identify individual DCs capable of presenting antigen to CD4+ T cells in the tdLN. These represent a small fraction of all DCs present in the tdLN and display a distinctive activated phenotype that includes production of cytokine IL-27, required for efficient T cell priming and tumor rejection. Tumor progression results in loss of effective priming of naive CD4+ T cells, downstream of transcriptional changes in DCs that are manifested already when they arrive at the tdLN. Collectively, our data reveal temporal shift in DC activation status over the course of the antitumor immune response.

Distinct components of nucleoside-modified messenger RNA vaccines cooperate to instruct efficient germinal center responses

“…As anticipated, the cells with the highest biotin expression did not fall in the cDC1 cluster and were enriched in the LC cluster and selected cDC2 groups (Groups 1,2 and 5; Figure 3H). Additionally, a GSEA approach confirmed the enrichment of a previously published LIPSTIC gene signature 37 in biotin + cells, further validating the antigenpresenting nature of the biotin + DC (Figure S3F and G).…”

“…Indeed, two biotin lo clusters associated with LNP-containing immunization stood out for their heightened expression of costimulatory molecules (CD80 and CD86). This outcome is substantially different from what was seen using the LIPSTIC approach to label DCs in a tumor model, where the activation was restricted to the biotin hi DCs that presented tumor antigens to CD4 T cells 37 . Taken together, these findings suggest that in the presence of a strong adjuvant, the need for T cell help to induce DC maturation is bypassed.…”

Reprogramming dendritic cells through the immunological synapse: A two‐way street

“…2). An interpretative caveat is that despite the disparity of the models, they all rely on the presence of OT-II CD4 + T cells as the interacting partner of the DC [43,48,56,[59][60][61]. To increase the degree of generality and robustness, it would be important to determine whether postsynaptic reprogramming occurs using "natural" CD4 + T-cell partners, that is, T cells bearing TCRs of various affinities for a wider array of peptide-loaded MHC-II molecules.…”

“…Also, nonspecific antigen‐dependent CD40‐CD40L interactions and labeling may take place at longer timepoints [56]. This system allows tracking DC:T‐cell interactions ex vivo and in vivo [58], and was used to demonstrate that antigen‐dependent interactions induce a specific activation state on interacting DCs that is essential for immune control of tumor progression [59]. It was also used to show that specific subsets of DCs underlie food tolerance and these populations become deregulated during gastrointestinal infection [60].…”

Ru(bpy)32+‐Enabled Cell‐Surface Photocatalytic Proximity Labeling toward More Efficient Capture of Physically Interacting Cells

“…Taken together, these results suggest that TCR-T cell-Ru can act as a "live" TCR multimer to decipher the affinities of different antigenic peptides to TCRs and resolve the heterogeneity of APC functions. [17]…”