Xiaofan Mao1,2, Dan Zhou3, Kairong Lin1,2, Beiying Zhang1,2, Juntao Gao4, Fei Ling5, Lewei Zhu3, Sifei Yu1,2, Peixian Chen3, Chuling Zhang1,2, Chunguo Zhang1,2, Guolin Ye3, Simon Fong6, Guoqiang Chen7, Wei Luo8,9. 1. Clinical Research Institute, The First People's Hospital of Foshan, Foshan, China. 2. Medical Engineering Technology Research and development center of Immune Repertoire in Foshan, The First People's Hospital of Foshan, Foshan, China. 3. Department of Breast Surgery, The First People's Hospital of Foshan, Foshan, China. 4. MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic and Systems Biology, BNRist; Department of Automation, Tsinghua University, Beijing, China. 5. School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China. 6. Department of Computer and Information Science, University of Macau, Macau SAR, China. 7. Department of Rheumatology and Immunology, The First People's Hospital of Foshan, Foshan, China. 13929981788@139.com. 8. Clinical Research Institute, The First People's Hospital of Foshan, Foshan, China. luowei_421@163.com. 9. Medical Engineering Technology Research and development center of Immune Repertoire in Foshan, The First People's Hospital of Foshan, Foshan, China. luowei_421@163.com.
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.
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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