Pan-cancer Analyses Refine the Single-Cell Portrait of Tumor-Infiltrating Dendritic Cells

Abstract Dendritic cells (DCs) are pivotal orchestrators of anti-tumor immunity. DC-based anti-tumor treatments are being actively developed, but effective clinical responses have not yet been achieved. Further exploration of DC heterogeneity in the tumor microenvironment (TME) and across cancer types could provide insights for developing DC-based immunotherapies. Here, we integrated single-cell RNA sequencing data of DCs from over 2,500 samples across 33 cancer types and established a comprehensive blueprint of human DCs. Several rare subsets of DCs infiltrated the tumors, including AXL+SIGLEC6+ (AS) DCs and Langerhans cell (LC)-like DCs, and displayed functional potentials marked with distinct transcriptomic characteristics. Computational analyses demonstrated that the LC-like subset could be an additional cellular origin of tumor-enriched LAMP3+ DCs and that distinct cellular origins are associated with the pleiotropic functional potentials of LAMP3+ DCs. Furthermore, this DC atlas enabled development of a machine learning model to guide DC annotation for subsequent single-cell analysis and prioritization of a valuable target for enhancing anti-tumor DC vaccination. This integrative resource provides a panoramic view to unravel the complexity of tumor-infiltrating DCs and offers valuable insights for developing therapies targeting DCs.