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IGH repertoire analysis at scale: deciphering the complexity of B cell infiltration and migration in esophageal squamous cell carcinoma

Cancer Gene Therapy volume 31, pages 131–147 (2024)Cite this article

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Abstract

Tumor-infiltrating B-lineage cells have become predictors of prognosis and immunotherapy responses in various cancers. However, limited knowledge about their infiltration and migration patterns has hindered the understanding of their anti-tumor functions. Here, we examined the immunoglobulin heavy chain (IGH) repertoires in 496 multi-regional tumor, 107 normal tissue, and 48 metastatic lymph node samples obtained from 107 patients with esophageal squamous cell carcinoma (ESCC). Our study revealed higher IgG-type B-lineage cells infiltration in tumors than in healthy tissue, which was associated with improved patient outcomes. Genes such as ACTN1, COL6A5, and pathways like focal adhesion, which shapes the physical structure of tumors, could affect B-lineage cell infiltration. Notably, the IGH sequence was used as an identity-tag to monitor B cell migration, and their infiltration schema within the tumor were depicted based on our multi-regional tumor specimens. This analysis revealed an escalation in B cell clones overlapped between metastatic lymph nodes and tumors. Therefore, the Lymph Node Activation Index was defined, which could predict the outcomes of patients with lymph node metastasis. This research introduces a novel framework for probing B cell infiltration and migration within the tumor microenvironment using large-scale transcriptome data, while simultaneously providing fresh perspectives on B cell immunology within ESCC.

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Fig. 1: Dissecting the composition of the IGH repertoire in the ESCC TME.
Fig. 2: Biased IGHV and IGHJ gene usage in the ESCC TME.
Fig. 3: High levels of B cell infiltration and IGH sequence richness are associated with better outcomes for ESCC patients.
Fig. 4: Tumor specific Genes and pathways correlated with IGHG1 richness in the ESCC TME.
Fig. 5: The similarity and heterogeneity of IGH repertoire across different tumor regions and tissues in ESCC patients.
Fig. 6: The mutation of IGH sequence in relation to the germline indicates the migration of B cells with tumor.
Fig. 7: The activation of B cells targeting metastatic tumors is linked to the prognosis of ESCC patients.

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Data availability

The IGH repertoire data derived from the multi-regional transcriptomic data used in this study have been submitted as supplementary materials to the article. Raw data can be obtained from the from the National Genomics Data Center (NGDC) with the project identifier “HRA005046” at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA005046. The validation transcriptomic raw data were obtained from our previously published ESCC cohort, which consisted of 155 paired tumor and normal samples. Detailed information and access to the data can be obtained from the National Genomics Data Center (NGDC) with the project identifier “HRA003107” at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA003107.

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Acknowledgements

This work was supported by funds of the Guangdong Basic and Applied Basic Research Foundation (2019B030302012), the National Key R&D Program of China (2021YFC2501001, 2022YFC3401002), Major Program of Shenzhen Bay Laboratory (S201101004), China Postdoctoral Science Foundation (2021M692160), Shenzhen Key Project of Science and Technology (JCYJ20200109120425045), Shenzhen Bay Laboratory Open Program (SZBL2020090501003), the National Natural Science Foundation of China (82341024, U21A20372, 81972613, 82172930, 82202990), and Shenzhen Science and Technology Innovation Commission Project (ZDSYS20190902092855097, KCXFZ20200201101050887, GJHZ20200731095207023). Many thanks to Shenzhen Bay Laboratory Supercomputing Center for providing the computing platform.

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Authors and Affiliations

  1. Cancer Institute, Department of Oncology, Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, Guangdong, 518035, China

    Longlong Wang, Yong Zhou, Heyang Cui, Xuehan Zhuang, Chen Cheng, Yongjia Weng, Shubin Wang, Yongping Cui & Weimin Zhang

  2. Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, Guangdong, 518028, China

    Longlong Wang, Yong Zhou, Heyang Cui, Xuehan Zhuang, Chen Cheng, Yongjia Weng, Shubin Wang, Yongping Cui & Weimin Zhang

  3. Key Laboratory of Cellular Physiology of the Ministry of Education, Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi, 030001, China

    Huijuan Liu & Yongping Cui

  4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China

    Xinghua Pan

  5. Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China

    Weimin Zhang

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Contributions

WMZ and YPC conceived and supervised the entire work. LLW conceived the study, performed the bioinformatics analyses, developed the methods, and wrote the manuscript. YZ, HYC, XHZ, CC, and YJW assisted the analysis. HJL, YJW, and HYC provided clinical records and related details of all patients. WMZ, XHP, YPC, and SBW contributed to critical revision of the article. All authors read and approved the final manuscript.

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Correspondence to Xinghua Pan, Yongping Cui or Weimin Zhang.

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This study was approved by the Institutional Review Boards of Shanxi Medical University and Shanxi Cancer Hospital (Shanxi, China). Informed consent was obtained from all the participants.

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Wang, L., Zhou, Y., Cui, H. et al. IGH repertoire analysis at scale: deciphering the complexity of B cell infiltration and migration in esophageal squamous cell carcinoma. Cancer Gene Ther 31, 131–147 (2024). https://doi.org/10.1038/s41417-023-00689-w

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