Macrophage-rich niches regulate T cell dynamics at the liver invasive margin during gallbladder cancer progression
Maolan Li, Zhaonan Liu, Shenbing Shan, Ziyao Jia, Yongsheng Li, Fatao Liu, Lina Lu, Shimei Qiu, Chen Li, Ziyi Wang, Siyuan Yan, Yuhao Zhao, Lili Gao, Zhiqing Yuan, Yuanding Liu, Jiyao Ma, Jiayi Feng, Pengxiao Geng, Yiming Li, Xiaojing Xu, Xinhua Lin, Changjun Liu, Zebing Liu, Wenguang Wu, Xiangsong Wu, Wei Gong, Yanjing Li, Dongxi Xiang, Yongning He, Yun Liu, Rong Shao, Kwan Man, Wu Wei, Yingbin Liu
Maolan Li, Zhaonan Liu, Shenbing Shan, Ziyao Jia, Yongsheng Li, Fatao Liu, Lina Lu, Shimei Qiu, Chen Li, Ziyi Wang, Siyuan Yan, Yuhao Zhao, Lili Gao, Zhiqing Yuan, Yuanding Liu, Jiyao Ma, Jiayi Feng, Pengxiao Geng, Yiming Li, Xiaojing Xu, Xinhua Lin, Changjun Liu, Zebing Liu, Wenguang Wu, Xiangsong Wu, Wei Gong, Yanjing Li, Dongxi Xiang, Yongning He, Yun Liu, Rong Shao, Kwan Man, Wu Wei, Yingbin Liu
View: Text | PDF
Research Article Immunology Oncology

Macrophage-rich niches regulate T cell dynamics at the liver invasive margin during gallbladder cancer progression

Abstract

Liver invasion is one of the most frequent events in the progression of gallbladder cancer (GBC). However, the cellular and pathological role of the tumor-liver–interface microenvironment in liver invasion is still enigmatic. Here, we applied single-cell and spatial transcriptomics to systematically investigate the cellular component and gene expression regulation of the microenvironment from the tumor to the liver, specifically the invasive boundary. Our analyses revealed that CXCL9+ macrophage–rich immune cell niches were accumulated in the tumor-liver invasive margin, where 2 subclasses of the CXCL9+ immune cell niches, CXCL9+TRAC+ (CT) and CXCL9+C1QB+ (CC) niches, were identified. CD8+ T cells were recruited by CXCL9+ macrophages through CXCL9-CXCR3 interaction in the CT niche, which was located adjacent to the liver. Moreover, the CC niche was proximal to the tumor core, where tumor cells induced CD8+ T cell exhaustion via LGALS4 expression. In addition, our cohort study showed that high CXCL9 and low LGALS4 in the liver invasion margin demonstrated a favorable prognosis and better responses to anti–PD-1 immunotherapy for patients with gallbladder cancer. Altogether, these findings demonstrate novel cellular and molecular mechanisms underlying liver invasion and offer clinical value for immunotherapies.

Authors

Maolan Li, Zhaonan Liu, Shenbing Shan, Ziyao Jia, Yongsheng Li, Fatao Liu, Lina Lu, Shimei Qiu, Chen Li, Ziyi Wang, Siyuan Yan, Yuhao Zhao, Lili Gao, Zhiqing Yuan, Yuanding Liu, Jiyao Ma, Jiayi Feng, Pengxiao Geng, Yiming Li, Xiaojing Xu, Xinhua Lin, Changjun Liu, Zebing Liu, Wenguang Wu, Xiangsong Wu, Wei Gong, Yanjing Li, Dongxi Xiang, Yongning He, Yun Liu, Rong Shao, Kwan Man, Wu Wei, Yingbin Liu

×

Figure 4

Cellular composition of the Immu subniches.

Options: View larger image (or click on image) Download as PowerPoint
Cellular composition of the Immu subniches. (A) Average cell abundance o...
(A) Average cell abundance of macrophages and T cells enriched in tumor-liver invasive margin (TL) in different spatial layers. (B) Ranking of the correlation coefficient between CXCL9+ macrophages (M_CXCL9) and other cell states in TL. Dot size represented the cell number of each cell state in TL. (C) Representative mIHC staining of M_CXCL9 and CXCL13+ CD8+ T cells (CD8T_CXCL13) in TL. Scale bar: 100 μm (upper) μm (lower). (D) Spatial plot of cell type distribution inferred by the FindTransferAnchors method in the TL slide using Visium HD. The black line represents the liver-tumor boundary. (E) Spatial gene expression profile detected with Visium HD. The black line represents the liver-tumor boundary. (F) Spatial density plot of cell substates distribution predicted by the FindTransferAnchors method. Dots indicate inferred cell substates, colored by prediction score. White contour lines depict prediction score density. Black line marks liver-tumor boundary. (G) Ratio of CD8T_CXCL13 versus proliferative MKI67+ CD8+ T cells (CD8T_MKI67) in CXCL9+C1QB+ (CC) and CXCL9+TRAC+ (CT) niches. (H) Schematic picture of M_CXCL9 and CD8+ T cell distribution in CC and CT niches. See also Supplemental Figure 9.