Yang, HaitangHaitangYangSun, BeibeiBeibeiSunFan, LiwenLiwenFanMa, WenyanWenyanMaXu, KeKeXuHall, Sean R RSean R RHallWang, ZhexinZhexinWangSchmid, RalphRalphSchmidPeng, Ren-WangRen-WangPengMarti, ThomasThomasMarti0000-0003-3005-220XGao, WenWenGaoXu, JianlinJianlinXuYang, WeiweiWeiweiYangYao, FengFengYao2024-10-112024-10-112022-03-28https://boris-portal.unibe.ch/handle/20.500.12422/85084Rationale: 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.enTHBS2 cancer-associated fibroblast early-stage lung adenocarcinoma exosome immunotherapy600 - Technology::610 - Medicine & healtharticle10.48350/1700333554775010.7150/thno.69590