Single-cell mapping reveals several immune subsets associated with liver metastasis of pancreatic ductal adenocarcinoma

Ze Zhang; Xiao-Qiang Zhu; Feng Yang; Nan-Nan Lai; Le Zhu; Kathryn Cole; Bei-Yuan Hu; Tian-En Li; Ying Zhu; Lu-Min Zhang; Shun Wang; Yan Zheng; Huarong Mao; Yue Zhao; Christiane Bruns; Razi Vago; Bo Tu; Jason W H Wong; De-Liang Fu; Lun-Xiu Qin; Qiong-Zhu Dong

doi:10.1016/j.medj.2023.07.010

Single-cell mapping reveals several immune subsets associated with liver metastasis of pancreatic ductal adenocarcinoma

Med. 2023 Oct 13;4(10):728-743.e7. doi: 10.1016/j.medj.2023.07.010. Epub 2023 Aug 25.

Authors

Ze Zhang¹, Xiao-Qiang Zhu², Feng Yang³, Nan-Nan Lai⁴, Le Zhu¹, Kathryn Cole⁵, Bei-Yuan Hu¹, Tian-En Li¹, Ying Zhu¹, Lu-Min Zhang⁴, Shun Wang¹, Yan Zheng¹, Huarong Mao⁴, Yue Zhao⁶, Christiane Bruns⁶, Razi Vago⁷, Bo Tu⁸, Jason W H Wong⁹, De-Liang Fu¹⁰, Lun-Xiu Qin¹¹, Qiong-Zhu Dong¹²

Affiliations

¹ Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
² State Key Laboratory for Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China.
³ Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
⁴ Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, China.
⁵ Division of Oncology and Hematology, University of Nebraska Medical Center, Omaha, NE, USA.
⁶ General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany.
⁷ Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
⁸ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address: tutumakmdanderson@gmail.com.
⁹ School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China. Electronic address: jwhwong@hku.hk.
¹⁰ Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: surgeonfu@163.com.
¹¹ Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: qinlx@fudan.edu.cn.
¹² Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer, Minhang Hospital, Fudan University, Shanghai, China. Electronic address: qzhdong@fudan.edu.cn.

PMID: 37633269
DOI: 10.1016/j.medj.2023.07.010

Abstract

Background: Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive.

Methods: Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry.

Findings: High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103⁺PD-1⁺CD39⁺ T cells with cytotoxic and exhausted functional status and an increased proportion of CD73⁺ macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC.

Conclusions: Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy.

Funding: This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.

Keywords: T cell; Translation to humans; macrophage; metastasis; pancreatic ductal adenocarcinoma; tumor microenvironment.

MeSH terms

Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / pathology
China
Ecosystem
Humans
Liver Neoplasms*
Pancreatic Neoplasms* / drug therapy
Tumor Microenvironment