CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells

Myung-Chul Kim; Nicholas Borcherding; Kawther K Ahmed; Andrew P Voigt; Ajaykumar Vishwakarma; Ryan Kolb; Paige N Kluz; Gaurav Pandey; Umasankar De; Theodore Drashansky; Eric Y Helm; Xin Zhang; Katherine N Gibson-Corley; Julia Klesney-Tait; Yuwen Zhu; Jinglu Lu; Jinsong Lu; Xian Huang; Hongrui Xiang; Jinke Cheng; Dongyang Wang; Zheng Wang; Jian Tang; Jiajia Hu; Zhengting Wang; Hua Liu; Mingjia Li; Haoyang Zhuang; Dorina Avram; Daohong Zhou; Rhonda Bacher; Song Guo Zheng; Xuefeng Wu; Yousef Zakharia; Weizhou Zhang

doi:10.1038/s41467-021-26091-4

CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells

Nat Commun. 2021 Oct 1;12(1):5764. doi: 10.1038/s41467-021-26091-4.

Authors

Myung-Chul Kim^#^{1

2}, Nicholas Borcherding^#^{3

4

5}, Kawther K Ahmed^#^{3

6}, Andrew P Voigt^#⁵, Ajaykumar Vishwakarma^{4

7}, Ryan Kolb^{1

2}, Paige N Kluz³, Gaurav Pandey^{3

8}, Umasankar De^{1

2}, Theodore Drashansky⁹, Eric Y Helm⁹, Xin Zhang^{2

10}, Katherine N Gibson-Corley¹¹, Julia Klesney-Tait¹², Yuwen Zhu¹³, Jinglu Lu¹⁴, Jinsong Lu¹⁵, Xian Huang¹⁵, Hongrui Xiang¹⁵, Jinke Cheng^{16

17}, Dongyang Wang¹⁸, Zheng Wang¹⁸, Jian Tang¹⁸, Jiajia Hu¹⁹, Zhengting Wang²⁰, Hua Liu²⁰, Mingjia Li²¹, Haoyang Zhuang²¹, Dorina Avram^{2

9

22}, Daohong Zhou^{2

10}, Rhonda Bacher²³, Song Guo Zheng²⁴, Xuefeng Wu^{25

26

27

28}, Yousef Zakharia²⁹, Weizhou Zhang^{30

31

32}

Affiliations

¹ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA.
² UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA.
³ Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA.
⁴ Cancer Biology Graduate Program, University of Iowa, Iowa City, IA, 52242, USA.
⁵ Medical Scientist Training Program, University of Iowa, Iowa City, IA, 52242, USA.
⁶ College of Pharmacy, University of Baghdad, Department of Pharmaceutics, Baghdad, 10071, Iraq.
⁷ Department of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, IA52242, USA.
⁸ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
⁹ Department of Anatomy and Cell Biology, University of Florida College of Medicine, 32610, Gainesville, FL, 32610, USA.
¹⁰ Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Fl, 32610, USA.
¹¹ Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232-2130, USA.
¹² Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
¹³ Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
¹⁴ Department of Breast Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, 200127, China.
¹⁵ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
¹⁶ 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 Jiao Tong University School of Medicine, Shanghai, 200025, China.
¹⁷ State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
¹⁸ Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
¹⁹ Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
²⁰ Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
²¹ Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Florida, 1600 Archer Road, Gainesville, FL, 32610-0275, USA.
²² Department of Immunology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
²³ Department of Biostatistics, University of Florida, Gainesville, FL, 32610, USA.
²⁴ Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, 43210, USA.
²⁵ Department of Breast Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, 200127, China. xuefengwu@shsmu.edu.cn.
²⁶ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. xuefengwu@shsmu.edu.cn.
²⁷ 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 Jiao Tong University School of Medicine, Shanghai, 200025, China. xuefengwu@shsmu.edu.cn.
²⁸ Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. xuefengwu@shsmu.edu.cn.
²⁹ Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232-2130, USA. yousef-zakharia@uiowa.edu.
³⁰ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA. zhangw@ufl.edu.
³¹ UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA. zhangw@ufl.edu.
³² Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA. zhangw@ufl.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Carcinogenesis / genetics
Carcinogenesis / pathology
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / immunology
Carcinoma, Renal Cell / pathology
GPI-Linked Proteins / deficiency
GPI-Linked Proteins / metabolism*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Homeostasis*
Humans
Isoantigens / metabolism*
Kidney Neoplasms / genetics
Kidney Neoplasms / immunology
Kidney Neoplasms / pathology
Lymphocytes, Tumor-Infiltrating / metabolism*
Mice
Mice, Knockout
Prognosis
Receptors, Cell Surface / deficiency
Receptors, Cell Surface / metabolism*
Single-Cell Analysis
T-Lymphocytes, Regulatory / metabolism*
Transcription, Genetic

Substances

CD177 protein, human
Cd177 protein, mouse
GPI-Linked Proteins
Isoantigens
Receptors, Cell Surface

Abstract

Publication types

MeSH terms

Substances

Grants and funding