Spatial analysis of stromal signatures identifies invasive front carcinoma-associated fibroblasts as suppressors of anti-tumor immune response in esophageal cancer

Journal of Experimental & Clinical Cancer Research

Research

Hai-Feng Zhang¹  Fa-Min Zeng²  Zhan-Yu Li²  Ye Liu²  Shao-Hong Wang³  Xiu-E Xu⁴  Xiao-Xiao Pang⁴  Qing-Feng Huang⁴  Li-Yan Xu⁴  Wen-Jun Shen⁵  Yang Chen⁶  Shuai-Xia Yu⁷  Jian-Zhong He⁸  En-Min Li⁹  Jian-Yi Wu⁹ 

[1] Department of Pathology and Laboratory Medicine, University of British Columbia, V5Z 1L3, Vancouver, British Columbia, Canada;Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-Sen University, 519000, Zhuhai, Guangdong Province, People’s Republic of China;Departments of Pathology, Shantou Central Hospital, 515041, Shantou, Guangdong, People’s Republic of China;Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Cancer Research Center, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Department of Bioinformatics, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Department of Pathology, First People’s Hospital of Yunnan Province, 650032, Kunming, Yunnan Province, China;Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Department of Pathology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, 610072, Chengdu, China;Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Department of Pathology, The Fifth Affiliated Hospital, Sun Yat-Sen University, 519000, Zhuhai, Guangdong Province, People’s Republic of China;Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, 515041, Shantou, Guangdong, People’s Republic of China;

关键词: TME;    Carcinoma-associated fibroblast;    Macrophage;    Prognostic model;    Esophageal squamous cell carcinoma;   

DOI  :  10.1186/s13046-023-02697-y

 received in 2023-01-12, accepted in 2023-05-03,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundIncreasing evidence indicates that the tumor microenvironment (TME) is a crucial determinant of cancer progression. However, the clinical and pathobiological significance of stromal signatures in the TME, as a complex dynamic entity, is still unclear in esophageal squamous cell carcinoma (ESCC).MethodsHerein, we used single-cell transcriptome sequencing data, imaging mass cytometry (IMC) and multiplex immunofluorescence staining to characterize the stromal signatures in ESCC and evaluate their prognostic values in this aggressive disease. An automated quantitative pathology imaging system determined the locations of the lamina propria, stroma, and invasive front. Subsequently, IMC spatial analyses further uncovered spatial interaction and distribution. Additionally, bioinformatics analysis was performed to explore the TME remodeling mechanism in ESCC. To define a new molecular prognostic model, we calculated the risk score of each patient based on their TME signatures and pTNM stages.ResultsWe demonstrate that the presence of fibroblasts at the tumor invasive front was associated with the invasive depth and poor prognosis. Furthermore, the amount of α-smooth muscle actin (α-SMA)+ fibroblasts at the tumor invasive front positively correlated with the number of macrophages (MØs), but negatively correlated with that of tumor-infiltrating granzyme B+ immune cells, and CD4+ and CD8+ T cells. Spatial analyses uncovered a significant spatial interaction between α-SMA+ fibroblasts and CD163+ MØs in the TME, which resulted in spatially exclusive interactions to anti-tumor immune cells. We further validated the laminin and collagen signaling network contributions to TME remodeling. Moreover, compared with pTNM staging, a molecular prognostic model, based on expression of α-SMA+ fibroblasts at the invasive front, and CD163+ MØs, showed higher accuracy in predicting survival or recurrence in ESCC patients. Regression analysis confirmed this model is an independent predictor for survival, which also identifies a high-risk group of ESCC patients that can benefit from adjuvant therapy.ConclusionsOur newly defined biomarker signature may serve as a complement for current clinical risk stratification approaches and provide potential therapeutic targets for reversing the fibroblast-mediated immunosuppressive microenvironment.

【 授权许可】

CC BY   
© The Author(s) 2023

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