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

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

doi:10.1038/s41467-021-26091-4

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.

Highlights

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
Analysis of TI Treg cells using single-cell RNA sequencing from cells from renal clear cell carcinoma (ccRCC) patients
Using our newly developed ccRCC single cell RNA sequencing dataset including 13,433 peripheral blood (PB) and 12,239 TI cells, we identified a cluster of Treg cells based on the expression of forkhead box P3 (FOXP3) and CD25 (IL2RA) (Fig. 1a, b), containing 160 PB and 574 TI Treg cells

Summary

Introduction

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. CD177, a cell surface protein normally expressed on neutrophil, is expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Treg cells play an indispensable role in maintaining normal immune homeostasis and peripheral tolerance. Their suppressive activity in the tumor microenvironment is associated with the loss of anti-tumor immunity[1], which provides the rationale for the development of Treg-targeted immunotherapy[2]. Recent studies unveiled functional heterogeneity of FOXP3+ Treg cells in peripheral blood (PB)[9], as well as in different tumor types including colorectal cancer[10] and glioma[11]. We further found that CD177 expressed by cancer cells has tumorsuppressive functions via regulating β-catenin activation[20]

Methods

Results

Conclusion