Abstract

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy.

Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.

Details

Title
CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells
Author
Kim, Myung-Chul 1 ; Borcherding, Nicholas 2 ; Ahmed, Kawther K 3   VIAFID ORCID Logo  ; Voigt, Andrew P 4   VIAFID ORCID Logo  ; Vishwakarma Ajaykumar 5 ; Kolb, Ryan 1 ; Kluz, Paige N 6 ; Pandey Gaurav 7 ; Umasankar, De 1 ; Drashansky Theodore 8   VIAFID ORCID Logo  ; Helm, Eric Y 8 ; Zhang, Xin 9   VIAFID ORCID Logo  ; Gibson-Corley, Katherine N 10 ; Klesney-Tait Julia 11 ; Zhu, Yuwen 12   VIAFID ORCID Logo  ; Lu Jinglu 13   VIAFID ORCID Logo  ; Lu, Jinsong 14 ; Huang, Xian 14 ; Xiang Hongrui 14 ; Cheng Jinke 15   VIAFID ORCID Logo  ; Wang, Dongyang 16 ; Wang, Zheng 16 ; Tang, Jian 16 ; Hu Jiajia 17 ; Wang Zhengting 18 ; Liu, Hua 18 ; Li, Mingjia 19 ; Zhuang Haoyang 19 ; Avram Dorina 20 ; Zhou, Daohong 9   VIAFID ORCID Logo  ; Bacher, Rhonda 21   VIAFID ORCID Logo  ; Zheng Song Guo 22 ; Wu, Xuefeng 23   VIAFID ORCID Logo  ; Zakharia Yousef 10   VIAFID ORCID Logo  ; Zhang Weizhou 24   VIAFID ORCID Logo 

1  University of Florida, Department of Pathology, Immunology and Laboratory Medicine, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091); University of Florida, UF Health Cancer Center, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091) 
2  University of Iowa, Department of Pathology, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294); University of Iowa, Cancer Biology Graduate Program, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294); University of Iowa, Medical Scientist Training Program, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
3  University of Iowa, Department of Pathology, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294); University of Baghdad, Department of Pharmaceutics, College of Pharmacy, Baghdad, Iraq (GRID:grid.411498.1) (ISNI:0000 0001 2108 8169) 
4  University of Iowa, Medical Scientist Training Program, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
5  University of Iowa, Cancer Biology Graduate Program, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294); University of Iowa, Department of Pharmaceutics and Translational Therapeutics, College of Pharmacy, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
6  University of Iowa, Department of Pathology, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
7  University of Iowa, Department of Pathology, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294); Washington University School of Medicine, Department of Radiation Oncology, St. Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
8  University of Florida College of Medicine, 32610, Department of Anatomy and Cell Biology, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091) 
9  University of Florida, UF Health Cancer Center, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091); University of Florida, Department of Pharmacodynamics, College of Pharmacy, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091) 
10  Vanderbilt University Medical Center, Department of Pathology, Microbiology & Immunology, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
11  University of Iowa, Department of Internal Medicine, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
12  University of Colorado Anschutz Medical Campus, Department of Surgery, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X) 
13  Shanghai Jiao Tong University School of Medicine, Shanghai, Department of Breast Surgery, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
14  Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
15  Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
16  Shanghai Jiao Tong University, Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
17  Shanghai Jiao Tong University School of Medicine, Department of Nuclear Medicine, Ruijin Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
18  Shanghai Jiao Tong University School of Medicine, Department of Gastroenterology, Ruijin Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
19  University of Florida, Department of Medicine, Division of Rheumatology & Clinical Immunology, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091) 
20  University of Florida, UF Health Cancer Center, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091); University of Florida College of Medicine, 32610, Department of Anatomy and Cell Biology, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091); Moffitt Cancer Center, Department of Immunology, Tampa, USA (GRID:grid.468198.a) (ISNI:0000 0000 9891 5233) 
21  University of Florida, Department of Biostatistics, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091) 
22  Ohio State University College of Medicine and Wexner Medical Center, Department of Internal Medicine, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
23  Shanghai Jiao Tong University School of Medicine, Shanghai, Department of Breast Surgery, Renji Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Biochemistry and Molecular Cell Biology, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); Shanghai Jiao Tong University School of Medicine, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293) 
24  University of Florida, Department of Pathology, Immunology and Laboratory Medicine, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091); University of Florida, UF Health Cancer Center, Gainesville, USA (GRID:grid.15276.37) (ISNI:0000 0004 1936 8091); University of Iowa, Department of Pathology, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-26091-4
ProQuest document ID
2578272655
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.