Theranostics 2022; 12(7):3104-3130. doi:10.7150/thno.69590 This issue

Research Paper

Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma

Haitang Yang1*, Beibei Sun2*, Liwen Fan1*, Wenyan Ma3*, Ke Xu1, Sean R. R. Hall4, Zhexin Wang1, Ralph A. Schmid5, Ren-Wang Peng5, Thomas M. Marti5, Wen Gao6, Jianlin Xu7✉, Weiwei Yang8✉, Feng Yao1✉

1. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University; Shanghai, 200030, People's Republic of China.
2. Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University; Shanghai, 200030, People's Republic of China.
3. Clinical Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.
4. Wyss Institute for Biologically Inspired Engineering, Harvard University; United States.
5. Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern; Bern, 3010, Switzerland.
6. Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, China.
7. Department of Respiratory Medicine, Shanghai Chest Hospital, Jiao Tong University; Shanghai, 200030, People's Republic of China.
8. School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, People's Republic of China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Yang H, Sun B, Fan L, Ma W, Xu K, Hall SRR, Wang Z, Schmid RA, Peng RW, Marti TM, Gao W, Xu J, Yang W, Yao F. Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma. Theranostics 2022; 12(7):3104-3130. doi:10.7150/thno.69590. Available from https://www.thno.org/v12p3104.htm

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Abstract

Graphic abstract

Rationale: Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear.

Methods: We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype.

Results: We identified and validated THBS2, at multi-omic levels, as a tumor size-independent biomarker that robustly predicted post-surgical survival in multiple independent clinical cohorts of early-stage LUAD. Furthermore, scRNA-seq data revealed that THBS2 is exclusively derived from a specific cancer-associated fibroblast (CAF) subset that is distinct from CAFs defined by classical markers. Interestingly, our data demonstrated that THBS2 was preferentially secreted via exosomes in early-stage LUAD tumors with high aggressiveness, and its levels in the peripheral plasma associated with short recurrence-free survival. Further characterization showed that THBS2-high early-stage LUAD was characterized by suppressed antitumor immunity. Specifically, beyond tumor cells, THBS2+ CAFs mainly interact with B and CD8+ T lymphocytes as well as macrophages within tumor microenvironment of early-stage LUAD, and THBS2-high LUAD was associated with decreased immune cell infiltrates but increased immune exhaustion marker. Clinically, high THBS2 expression predicted poor response to immunotherapies and short post-treatment survival of patients. Finally, THBS2 recombinant protein suppressed ex vivo T cells proliferation and promoted in vivo LUAD tumor growth and distant micro-metastasis.

Conclusions: Our multi-level analyses uncovered tumor-specific THBS2+ CAFs as a key orchestrator promoting aggressiveness in early-stage LUAD.

Keywords: early-stage lung adenocarcinoma, THBS2, exosome, cancer-associated fibroblast, immunotherapy