PT  - JOURNAL ARTICLE
AU  - Son, Jimin
AU  - Cho, Jae-Won
AU  - Park, Hyo Jin
AU  - Moon, Jihyun
AU  - Park, Seyeon
AU  - Lee, Hoyoung
AU  - Lee, Jeewon
AU  - Kim, Gamin
AU  - Park, Su-Myeong
AU  - Lira, Sergio A.
AU  - Mckenzie, Andrew N.
AU  - Kim, Hye Young
AU  - Choi, Cheol Yong
AU  - Lim, Yong Taik
AU  - Park, Seong Yong
AU  - Kim, Hye Ryun
AU  - Park, Su-Hyung
AU  - Shin, Eui-Cheol
AU  - Lee, Insuk
AU  - Ha, Sang-Jun
TI  - Tumor-Infiltrating Regulatory T-cell Accumulation in the Tumor Microenvironment Is Mediated by IL33/ST2 Signaling
AID  - 10.1158/2326-6066.CIR-19-0828
DP  - 2020 Nov 01
TA  - Cancer Immunology Research
PG  - 1393--1406
VI  - 8
IP  - 11
4099  - http://cancerimmunolres.aacrjournals.org/content/8/11/1393.short
4100  - http://cancerimmunolres.aacrjournals.org/content/8/11/1393.full
SO  - Cancer Immunol Res2020 Nov 01; 8
AB  - Regulatory T cells (Treg) are enriched in the tumor microenvironment (TME) and suppress antitumor immunity; however, the molecular mechanism underlying the accumulation of Tregs in the TME is poorly understood. In various tumor models, tumor-infiltrating Tregs were highly enriched in the TME and had significantly higher expression of immune checkpoint molecules. To characterize tumor-infiltrating Tregs, we performed bulk RNA sequencing (RNA-seq) and found that proliferation-related genes, immune suppression–related genes, and cytokine/chemokine receptor genes were upregulated in tumor-infiltrating Tregs compared with tumor-infiltrating CD4+Foxp3− conventional T cells or splenic Tregs from the same tumor-bearing mice. Single-cell RNA-seq and T-cell receptor sequencing also revealed active proliferation of tumor infiltrating Tregs by clonal expansion. One of these genes, ST2, an IL33 receptor, was identified as a potential factor driving Treg accumulation in the TME. Indeed, IL33-directed ST2 signaling induced the preferential proliferation of tumor-infiltrating Tregs and enhanced tumor progression, whereas genetic deletion of ST2 in Tregs limited their TME accumulation and delayed tumor growth. These data demonstrated the IL33/ST2 axis in Tregs as one of the critical pathways for the preferential accumulation of Tregs in the TME and suggests that the IL33/ST2 axis may be a potential therapeutic target for cancer immunotherapy.