Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types

Junho Kang, Jun Hyeong Lee, Hongui Cha, Jinhyeon An, Joonha Kwon, Seongwoo Lee, Seongryong Kim, Mert Yakup Baykan, So Yeon Kim, Dohyeon An, Ah-Young Kwon, Hee Jung An, Se-Hoon Lee (), Jung Kyoon Choi () and Jong-Eun Park ()
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Junho Kang: Korea Advanced Institute of Science and Technology
Jun Hyeong Lee: Korea Advanced Institute of Science and Technology
Hongui Cha: Sungkyunkwan University School of Medicine
Jinhyeon An: Korea Advanced Institute of Science and Technology
Joonha Kwon: Korea Advanced Institute of Science and Technology
Seongwoo Lee: Korea Advanced Institute of Science and Technology
Seongryong Kim: Korea Advanced Institute of Science and Technology
Mert Yakup Baykan: Korea Advanced Institute of Science and Technology
So Yeon Kim: Korea Advanced Institute of Science and Technology
Dohyeon An: Korea Advanced Institute of Science and Technology
Ah-Young Kwon: CHA University
Hee Jung An: CHA University
Se-Hoon Lee: Sungkyunkwan University School of Medicine
Jung Kyoon Choi: Korea Advanced Institute of Science and Technology
Jong-Eun Park: Korea Advanced Institute of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8887 TCGA, and 1261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n = 1261) including our lung cancer cohort (n = 497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.

Date: 2024
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DOI: 10.1038/s41467-024-48310-4

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