Specific lineage transition of tumor-associated macrophages elicits immune evasion of ascitic tumor cells in gastric cancer with peritoneal metastasis

作者：Yilin Li, Lei Jiang, Yang Chen, Yanyan Li, Jiajia Yuan, Jialin Lu, Zizhen Zhang, Shengde Liu, Xujiao Feng, Jiaxin Xiong, Yan Jiang, Xiaotian Zhang, Jian Li, Lin Shen · 发表于：Gastric Cancer · 年份：2024 · DOI：10.1007/s10120-024-01486-6 · 被引用次数：23 · 研究领域：Immune cells in cancer、Single-cell and spatial transcriptomics、Cancer Cells and Metastasis

Abstract Background Gastric cancer with peritoneal metastasis (PM-GC), recognized as one of the deadliest cancers. However, whether and how the tumor cell-extrinsic tumor microenvironment (TME) is involved in the therapeutic failure remains unknown. Thus, this study systematically assessed the immunosuppressive tumor microenvironment in ascites from patients with PM-GC, and its contribution to dissemination and immune evasion of ascites-disseminated tumor cells (aDTCs). Methods Sixty-three ascites and 43 peripheral blood (PB) samples from 51 patients with PM-GC were included in this study. aDTCs in ascites and circulating tumor cells (CTCs) in paired PB were immunophenotypically profiled. Using single-cell RNA transcriptional sequencing (scRNA-seq), crosstalk between aDTCs and the TME features of ascites was inspected. Further studies on the mechanism underlying aDTCs-immune cells crosstalk were performed on in vitro cultured aDTCs. Results Immune cells in ascites interact with aDTCs, prompting their immune evasion. Specifically, we found that the tumor-associated macrophages (TAMs) in ascites underwent a continuum lineage transition from cathepsin high (CTS high ) to complement 1q high (C1Q high ) TAM. CTS high TAM initially attracted the metastatic tumor cells to ascites, thereafter, transitioning terminally to C1Q high TAM to trigger overproliferation and immune escape of aDTCs. Mechanistically, we demonstrated that C1Q high TAMs significantly enhanced the expression of PD...