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

Authors

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

Published in

Nature communications. Volume 17. Issue 1. Aug 03, 2026. Epub Aug 03, 2026.

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.

PMID:
42547508
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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