Dendritic cell subsets in cancer immunity and tumor antigen sensing

Abstract

Dendritic cells (DCs) exhibit a specialized antigen-presenting function and play crucial roles in both innate and adaptive immune responses. Due to their ability to cross-present tumor cell-associated antigens to naïve T cells, DCs are instrumental in the generation of specific T-cell-mediated antitumor effector responses in the control of tumor growth and tumor cell dissemination. Within an immunosuppressive tumor microenvironment, DC antitumor functions can, however, be severely impaired. In this review, we focus on the mechanisms of DC capture and activation by tumor cell antigens and the role of the tumor microenvironment in shaping DC functions, taking advantage of recent studies showing the phenotype acquisition, transcriptional state and functional programs revealed by scRNA-seq analysis. The therapeutic potential of DC-mediated tumor antigen sensing in priming antitumor immunity is also discussed.

Keywords: Dendritic cell subsets; Immune cell death; Innate immune sensing; Migration; Tumor microenvironment; Tumor-derived extracellular vesicles.

Fig. 1

Pathogen-sensing machinery expression in human DC populations in the human myeloid scRNA atlas. A Visualization of PhenoGraph clusters on an MNP-VERSE UMAP plot following the coordinates presented by Mulder et al., 2021. Briefly, MNP-VERSE was downloaded from https://github.com/gustaveroussy/FG-Lab, and the data were explored with Seurat v4.2 (Hao and Hao et al. 2021, 10.1016/j.cell.2021.04.048). For simplicity, monocyte and macrophage clusters were unified. Bottom left, cells derived from cells enriched in cell cycle-related genes were unlabelled. B DotPlot presenting the normalized expression of TLRs from the MNP-VERSE. C DotPlot presenting the normalized expression of dsDNA machinery sensing from the MNP-VERSE

Fig. 2

Lineage markers conserved between human and murine lung tumor-infiltrating DCs. Top panel, list of the 10 most highly expressed marker genes shared between human and mouse DC populations based on comparisons described in Zilionis et al., 2019. DC3s are missing due to the lack of a known homolog in mice. Bottom panel, schematic representation of the lung tumor microenvironment showing tumor-infiltrating DC populations. Adapted from “Tumor Microenvironment”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates

Fig. 3

Role of immunogenic cell death in dendritic cell (DC) activation. In response to different inducers of ICD, tumor cells expose/secrete several damage-associated molecular patterns (DAMPs) that interact with DCs. PDT photodynamic therapy, ECP extracorporeal photochemotherapy, HHP high hydrostatic pressure, CRT calreticulin, ANXA1 annexin A1, FPR1 formyl peptide receptor 1, HSP heat-shock protein, P2RY2 purinergic receptor P2Y2, P2RX7 purinergic receptor P2X7, HMGB1 high-mobility group box 1, TLR Toll-like receptor, IFN interferon, IFNAR type I interferon receptor. Created with BioRender.com

Fig. 4

Tumor-derived extracellular vesicles (EVs) regulate the antigen-presenting properties of DCs. A EV subpopulations are represented based on size and origin. Exosomes are the most extensively studied tumor-derived EVs. Very few authors have addressed the role of different EV subpopulations in modulating DC biology in tumors. B Tumor-derived EVs have been shown to mediate two main and apparently contradictory functions in DCs, i.e., increased (depicted on the left) or decreased tumor antigen presentation (right side). The image summarizes the different regulatory mechanisms in a single EV different identified in specific tumor types and EV subpopulations. MVB multivesicular body, ILVs intraluminal vesicles, TAA tumor-associated antigen, FA fatty acid, palmit. proteins palmitoylated proteins, ARG1 arginase 1. Created with BioRender.com