DKK1+ tumor cells inhibited the infiltration of CCL19+ fibroblasts and plasma cells contributing to worse immunotherapy response in hepatocellular carcinoma

作者：Guangyu Fan, Ruyun Gao, Tongji Xie, Lin Li, Le Tang, Han Xiao-hong, Yuankai Shi · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-07195-3 · 被引用次数：16 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Chemokine receptors and signaling

Intra-tumor immune infiltration plays a pivotal role in the interaction with tumor cells in hepatocellular carcinoma (HCC). However, its phenotype and related spatial structure remained elusive. To address these limitations, we conducted a comprehensive study combining spatial data (38,191 spots from eight samples) and single-cell data (56,022 cells from 20 samples). Our analysis revealed two distinct infiltration patterns: immune exclusion and immune activation. Plasma cells emerged as the primary cell type within intra-tumor immune clusters. Notably, we observed the co-location of CCL19+ fibroblasts with plasma cells, which secrete chemokines and promote T-cell activation and leukocyte migration. Conversely, in immune-exclusion samples, this co-location was primarily observed in the adjacent normal area. This co-localization correlated with T cell infiltration and the formation of tertiary lymphoid structures, validated by multiplex immunofluorescence conducted on twenty HCC samples. Both CCL19+ fibroblasts and plasma cells were associated with favorable survival outcomes. In an immunotherapy cohort, HCC patients who responded favorably exhibited higher infiltration of CCL19+ fibroblasts and plasma cells. Additionally, we observed the accumulation of DKK1+ tumor cells within the tumor area in immune-exclusion samples, particularly at the tumor boundary, which inhibited the infiltration of CCL19+ fibroblasts and plasma cells into the tumor area. Furthermore, in immune-exclus...