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<p>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<sup>+</sup> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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

摘要

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.