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

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

Affiliations

¹ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA.
² Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA.
³ Medical Scientist Training Program, University of Iowa, Iowa City, IA, 52242, USA.
⁴ Cancer Biology Graduate Program, University of Iowa, Iowa City, IA, 52242, USA.
⁵ Department of Anatomy and Cell Biology, University of Florida College of Medicine, 32610, Gainesville, FL, 32610, USA.
⁶ UF Health Cancer Center, University of Florida, Gainesville, FL, 32610, USA.
⁷ Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232-2130, USA.
⁸ Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
⁹ Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
¹⁰ Department of Breast Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, 200127, China.
¹¹ Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
¹² 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.
¹³ Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
¹⁴ Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
¹⁵ Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
¹⁶ Department of Medicine, Division of Rheumatology & Clinical Immunology, University of Florida, 1600 Archer Road, Gainesville, FL, 32610-0275, USA.
¹⁷ Department of Biostatistics, University of Florida, Gainesville, FL, 32610, USA.
¹⁸ Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, 43210, USA.
¹⁹ Department of Breast Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, Shanghai, 200127, China. xuefengwu@shsmu.edu.cn.
²⁰ Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232-2130, USA. yousef-zakharia@uiowa.edu.
²¹ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, 32610, USA. zhangw@ufl.edu.

PMID: 34599187
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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.

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