Despite the crucial role of antigen presentation in immune checkpoint inhibitor (ICI) efficacy, its contribution and the mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear, representing a key knowledge gap in overcoming immune escape in its immunotherapy. This study explores how tumor antigen presentation and intercellular interactions in the tumor microenvironment (TME) drive ICI resistance using single-cell RNA sequencing (scRNA-seq). Publicly available scRNA-seq data from 24 ESCC patients treated with chemotherapy and ICIs were analyzed. Cell clustering, transcription factor regulation, cell–cell communication analysis, and KEGG/GO enrichment analyses were used to examine malignant cell heterogeneity, the relationship between antigen-presenting cells and ICI responses, and cell–cell interactions influencing anti-tumor response. Spatial relationships were validated through multiplex immunofluorescence. Malignant cells were classified by enrichment analyses into cNMF₁, cNMF₂, cNMF₃, and cNMF₄, with cNMF₄ showing antigen-presenting traits. Based on ICI response groups, cell–cell communication analysis revealed that in poor responders, the antigen presentation ability of tumors induced by treatment was enhanced, and mainly enriched in the MHC-I pathway. The crosstalk between Progenitor CD8 + Tex and hyper-Treg in the TME drove ICI resistance. Hyper-Treg likely regulated CD8 + T activation through the CLEC2C-KLRB1 axis, forming an inhibitory cell interaction network dominated by hyper-Treg, resulting in an overall strong immune suppression state of the TME in this population. The antigen-presenting malignant epithelial cells of ESCC exhibit significant interactions with various T cells in the TME. ICI resistance is closely associated with the crosstalk between progenitor CD8 + Tex and hyper-Treg, representing a promising target for personalized ESCC therapy.
Huang et al. (Thu,) studied this question.