Uncovering ectopic GC-like niches for tumor reactive lymphocyte priming in lung adenocarcinoma using Stereo-XCR-seq

T/B cell receptors (T/BCR), coordinating antigen-targeting immune response, play crucial roles in anti-tumor immune response. Tracking T and B cell clonal evolution in situ at single-cell resolution is essential for understanding the adaptive immune responses. To address the lack of tools for in situ single-cell T/BCR (XCR) sequencing, we develop Stereo-XCR-seq, an efficient method for retrieving and sequencing TCR and BCR from spatial transcriptome cDNA libraries at subcellular resolution. Stereo-XCR-seq enables high-fidelity, unbiased recovery of XCR sequences alongside spatial transcriptomics in extensive tissues, facilitating the identification of heterogeneous lymphoid aggregates with distinct clonal activities in situ. Using Stereo-XCR-seq, we uncover that IgG+ plasma cell aggregates display features of ectopic germinal center-like (GC-like) niches to select tumor-reactive clones from distal immature tertiary lymphoid structures in 11 lung adenocarcinoma (LUAD) tumors. The presence of these IgG+ plasma cell aggregates in LUAD indicates an improved anti-tumor immune surveillance and sensitivity towards immune checkpoint blockade (ICB) therapy. Collectively, Stereo-XCR-seq enables in situ single-cell profiling of T and B cell clonal activities and their interactions with local microenvironment, links tumor reactivity to intratumoral distribution of lymphocytes, and thus offers a versatile tool for dissecting lymphocyte clonal dynamics across human diseases. There is a lack of tools for in situ single cell T (TCR) and B cell receptor (BCR) sequencing. Here, the authors develop Stereo-XCR-seq for retrieving and sequencing TCR and BCR from spatial transcriptome cDNA libraries at subcellular resolution and apply it to lung adenocarcinoma.

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Journal
Nature Communications
Published
2026-08-03
DOI
https://doi.org/10.1038/s41467-026-75405-x
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
0.00

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article

Uncovering ectopic GC-like niches for tumor reactive lymphocyte priming in lung adenocarcinoma using Stereo-XCR-seq

Senyi Deng, Shengbao Suo, Francis Ka-Ming Chan, Jingying Zhou et al.
Nature Communications
Single-cell and spatial transcriptomics
article

Uncovering ectopic GC-like niches for tumor reactive lymphocyte priming in lung adenocarcinoma using Stereo-XCR-seq

Senyi Deng, Shengbao Suo, Francis Ka-Ming Chan, Jingying Zhou, Tao Zeng, Chuanyu Liu, Longqi Liu, Xubin Zheng, Jinwen Yin, Yin Yao, Xinxing Li, Yanying Guo, Zhidong Gao, Zhifang Wu, Young Li, Yingqi Dong, Xuan Dong, Zexian Zeng, Yuliang Dong, Qin Wu, Haoran Tao, Xin Liu, Hua Wang, Rong Ma, Xun Xu, Yu Feng, Yixin Yan, Chengwu Liu, Sen Hou, Fan Zhu, Xiaojuan Zhan, Xiaoyu Chen, Hui Zeng, Yang Zhang, Mengye Huang, Yi Liu, Li Zuo, Wenwen Zhou, Yong Hou, Zhong Liu, Haohang Yang, Xinlei Ai, Hanyong Sun
article en

Abstract

T/B cell receptors (T/BCR), coordinating antigen-targeting immune response, play crucial roles in anti-tumor immune response. Tracking T and B cell clonal evolution in situ at single-cell resolution is essential for understanding the adaptive immune responses. To address the lack of tools for in situ single-cell T/BCR (XCR) sequencing, we develop Stereo-XCR-seq, an efficient method for retrieving and sequencing TCR and BCR from spatial transcriptome cDNA libraries at subcellular resolution. Stereo-XCR-seq enables high-fidelity, unbiased recovery of XCR sequences alongside spatial transcriptomics in extensive tissues, facilitating the identification of heterogeneous lymphoid aggregates with distinct clonal activities in situ. Using Stereo-XCR-seq, we uncover that IgG+ plasma cell aggregates display features of ectopic germinal center-like (GC-like) niches to select tumor-reactive clones from distal immature tertiary lymphoid structures in 11 lung adenocarcinoma (LUAD) tumors. The presence of these IgG+ plasma cell aggregates in LUAD indicates an improved anti-tumor immune surveillance and sensitivity towards immune checkpoint blockade (ICB) therapy. Collectively, Stereo-XCR-seq enables in situ single-cell profiling of T and B cell clonal activities and their interactions with local microenvironment, links tumor reactivity to intratumoral distribution of lymphocytes, and thus offers a versatile tool for dissecting lymphocyte clonal dynamics across human diseases. There is a lack of tools for in situ single cell T (TCR) and B cell receptor (BCR) sequencing. Here, the authors develop Stereo-XCR-seq for retrieving and sequencing TCR and BCR from spatial transcriptome cDNA libraries at subcellular resolution and apply it to lung adenocarcinoma.

Nature CommunicationsVol. 17(1)
BGI Group (China) (CN), Shanxi Medical University (CN), Chinese University of Hong Kong (HK), Shanghai Jiao Tong University (CN), Anhui Medical University (CN), Peking University (CN), TCL (China) (CN), Sichuan University (CN), Renji Hospital (CN), West China Hospital of Sichuan University (CN), First Affiliated Hospital of Guangzhou Medical University (CN), Zhejiang Cancer Hospital (CN), Beijing Academy of Artificial Intelligence (CN), Netherlands Heart Registration (NL), Peking University People's Hospital (CN), First Hospital of Shanxi Medical University (CN), First Affiliated Hospital of Anhui Medical University (CN), Shenzhen Institutes of Advanced Technology (CN), Shenzhen Technology University (CN), State Key Laboratory of Respiratory Disease (CN), State Key Laboratory of Chemical Engineering (CN), Second Affiliated Hospital of Zhejiang University (CN), Tongji Hospital (CN), Center for Life Sciences (CN), Ministry of Education (KN), University of Chinese Academy of Sciences (CN), BGI Research (CN), Great Bay University, Huazhong University of Science and Technology (CN), Zhejiang University (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, National Science and Technology Major Project, National Key Research and Development Program of China
Openalex Percentile: Top 15%
Single-cell and spatial transcriptomics
DOIOpen Access PDFOpenAlex
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