CEACAM marks intratumoral Tregs that exhibited highly suppressive and activated phenotypes

Abstract

Abstract Regulatory T cells (Tregs) exert immunosuppressive functions and hamper anti-tumor immune responses in the tumor microenvironment. Understanding the heterogeneity of intratumoral Tregs, and how it changes with tumor progression, will provide clues regarding novel target molecules of Treg-directed therapies. Here we characterized the phenotypes and suppressive function of Tregs from tumor tissues of 42 patients with renal cell carcinoma using multicolor flow cytometry, RNA sequencing, and in vitro functional assay. We found that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was selectively expressed on intratumoral Tregs, while its expression on peripheral Tregs or other immune cells was minimal. CEACAM1 +intratumoral Tregs accumulated with tumor progression, while the CEACAM1 −subset did not. Notably, we found that CEACAM1 marked intratumoral Tregs that exhibited highly suppressive and activated phenotypes with substantial clonal expansion. Depletion of CEACAM1-expressing cells from tumor-infiltrating leukocytes led to increased effector functions of exhausted T cells. Moreover, CEACAM1 +cell depletion further enhanced anti-PD-1-–mediated reinvigoration of exhausted CD8 +T cells. Collectively, our results demonstrate that CEACAM1 delineates highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs.