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
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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

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Figure 2

Spatial distribution and molecular characteristics of immune cell niches.

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Spatial distribution and molecular characteristics of immune cell niches...
(A) Scheme of invasion boundary (BD) and distance to BD analysis method in POSST pipeline. (B) BD was identified in different tumor regions (TPT, T, TL) from patient 2. (C) Dynamic changes of 12 spatial niches in different tumor regions (TPT, T, TL). Each layer was about 100 μm in width. (D) Schematic of neighborhood score (NS), aggregation score (AS), and colocalization score (CS) definition for center spot x in POSST pipeline. NS, AS, and CS reflect the regional diversity of proximate niches, self-clustering tendency, and abundance of specific interniche spatial association, respectively. (E) Line graph ordering of the mean NS from spatial niches. (F) Box plot showing AS of the immune cell niche (Immu niche) in 5 sampling sites. ***P < 0.001. (G) Lollipop graph displaying the mean CS between the Immu niche and other spatial niches in TL. (H) Volcano plot showing differentially expressed genes in the immune-cell–related (Immu-related) niches. (I) Bar plot revealing gene ontology analysis in Immu niches. (J and K) CXCL9 expression (left) and AUCell score of the chemokine signaling pathway (right) in representative TL slides (J) and all samples (K). BD spots were labeled with hollow circles. (L) Representative CXCL9 IHC staining in a GBC tumor-liver invasion section. The left panel shows the entire interface; the right panel is a magnified view of the boxed area, highlighting the invasive boundary. Scale bars: 100 μm (left); 50 μm (right). (M) Bubble plot showing CXCL9 expression in distinct cell states from scRNA-seq. (N) Representative mIHC staining of tumor liver invasion tissue in the liver invasion model developed by GBC cell lines GBC/SD and ZJU0430 in nude mice. CXCL9+ macrophages were labeled with white arrows. See also Supplemental Figures 6 and 7.