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