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Single-cell and spatial transcriptome analyses revealed cell heterogeneity and immune environment alternations in metastatic axillary lymph nodes in breast cancer

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Abstract

Background

Tumor heterogeneity plays essential roles in developing cancer therapies, including therapies for breast cancer (BC). In addition, it is also very important to understand the relationships between tumor microenvironments and the systematic immune environment.

Methods

Here, we performed single-cell, VDJ sequencing and spatial transcriptome analyses on tumor and adjacent normal tissue as well as axillar lymph nodes (LNs) and peripheral blood mononuclear cells (PBMCs) from 8 BC patients.

Results

We found that myeloid cells exhibited environment-dependent plasticity, where a group of macrophages with both M1 and M2 signatures possessed high tumor specificity spatially and was associated with worse patient survival. Cytotoxic T cells in tumor sites evolved in a separate path from those in the circulatory system. T cell receptor (TCR) repertoires in metastatic LNs showed significant higher consistency with TCRs in tumor than those in nonmetastatic LNs and PBMCs, suggesting the existence of common neo-antigens across metastatic LNs and primary tumor cites. In addition, the immune environment in metastatic LNs had transformed into a tumor-like status, where pro-inflammatory macrophages and exhausted T cells were upregulated, accompanied by a decrease in B cells and neutrophils. Finally, cell interactions showed that cancer-associated fibroblasts (CAFs) contributed most to shaping the immune-suppressive microenvironment, while CD8+ cells were the most signal-responsive cells.

Conclusions

This study revealed the cell structures of both micro- and macroenvironments, revealed how different cells diverged in related contexts as well as their prognostic capacities, and displayed a landscape of cell interactions with spatial information.

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Availability of data and materials

All data generated in this study have been uploaded to Genome Sequence Archive (GSA, https://ngdc.cncb.ac.cn/) with accession number HRA002051 and OMIX001111 under the project of PRJCA008495. Supplementary files were listed as below: Supplementary patient information file: Supplementary Table file: Table S1–S8; Supplementary Figure file: Figure S1–S16.

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Funding

This work was funded by grants from the National Natural Science Foundation of China (81972335, 82103347), Basic and Applied Basic Research Fund of Guangdong Province (2019A1515110677, 2019A1515110676) and Foshan City Climbing Peak Plan (2019A004), Medical Engineering Technology Research and Development Center of Immune Repertoire in Foshan.

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Author notes

  1. Xiaofan Mao, Dan Zhou, Kairong Lin, and Beiying Zhang have contributed equally to this work.

Authors and Affiliations

  1. Clinical Research Institute, The First People’s Hospital of Foshan, Foshan, China

    Xiaofan Mao, Kairong Lin, Beiying Zhang, Sifei Yu, Chuling Zhang, Chunguo Zhang & Wei Luo

  2. Medical Engineering Technology Research and development center of Immune Repertoire in Foshan, The First People’s Hospital of Foshan, Foshan, China

    Xiaofan Mao, Kairong Lin, Beiying Zhang, Sifei Yu, Chuling Zhang, Chunguo Zhang & Wei Luo

  3. Department of Breast Surgery, The First People’s Hospital of Foshan, Foshan, China

    Dan Zhou, Lewei Zhu, Peixian Chen & Guolin Ye

  4. MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist; Department of Automation, Tsinghua University, Beijing, China

    Juntao Gao

  5. School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China

    Fei Ling

  6. Department of Computer and Information Science, University of Macau, Macau SAR, China

    Simon Fong

  7. Department of Rheumatology and Immunology, The First People’s Hospital of Foshan, Foshan, China

    Guoqiang Chen

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  1. Xiaofan Mao
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Contributions

XM constructed sequencing libraries, performed data analysis and wrote the manuscript. DZ collected the samples. KL, BZ, SY, ChulingZ and ChunguoZ prepared single cell suspensions. JG, FL and SF helped to revise the manuscript. LZ, PC and GY helped to communicate with patients. GC and WL supervised this study.

Corresponding authors

Correspondence to Guoqiang Chen or Wei Luo.

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This study was approved by the independent ethics committee at The First People’s Hospital of Foshan. All patients provided written informed consent to participate in the study.

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Mao, X., Zhou, D., Lin, K. et al. Single-cell and spatial transcriptome analyses revealed cell heterogeneity and immune environment alternations in metastatic axillary lymph nodes in breast cancer. Cancer Immunol Immunother 72, 679–695 (2023). https://doi.org/10.1007/s00262-022-03278-2

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