Seung Hyuck Jeon1, Minyong Kang2,3,4, Minwoo Jeon1, Youseung Chung1, A Reum Kim1, Yong Joon Lee1, Eui-Soon Kim1, Heejin Nam1, Junsik Park5, Jung-Yun Lee5, Eui-Cheol Shin1, Seong Il Seo2, and Su-Hyung Park1
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
2Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
3Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
4Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
5Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Republic of Korea.
S.H. Jeon and M. Kang contributed equally to this article.
Corresponding Authors: Su-Hyung Park; Seong Il Seo; and Eui-Cheol Shin
Purpose: 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.
Experimental design: From 42 patients with renal cell carcinoma and 5 patients with ovarian cancer, immune cells from tumor and peripheral blood were isolated. We performed multicolor flow cytometry and RNA-sequencing to characterize the phenotypes and heterogeneity of intratumoral Tregs. In vitro functional assays were performed to evaluate suppressive capacity of Tregs and effect of CEACAM1-mediated depletion. The CT26 tumor model was used to evaluate the association between intratumoral Tregs and tumor growth, and examine the in vivo role of CEACAM1+ intratumoral Tregs on anti-tumor immunity.
Results: 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 low. The 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 tumor-infiltrating T cells. Moreover, CEACAM1+ cell depletion further enhanced anti-PD-1--mediated reinvigoration of exhausted CD8+ T cells.
Conclusions: CEACAM1 marks highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs. These results may inform future studies on CEACAM1-mediated depletion in cancer patients.