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 CD4þFoxp3- 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.
Bibliographical noteFunding Information:
This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT; 2012H1A2A1016220, to J. Son; 2017R1A5A1014560, 2018M3A9H3024850, 2018R1A2A1A05076997, and 2019M3A9B6065221, to S-.J. Ha; 2019M3A9B6065192 and 2018R1A5A2025079, to I. Lee; and 2019M3A9B6065231, to H.R. Kim). J. Son, J.-W. Cho, H.J. Park, J. Moon, and S. Park are fellowship awardees by the BK21 PLUS program.
© 2020 American Association for Cancer Research.
All Science Journal Classification (ASJC) codes
- Cancer Research