Tumor-infiltrating regulatory T-cell accumulation in the tumor microenvironment is mediated by IL33/ST2 signaling

Jimin Son, Jae Won Cho, Hyo Jin Park, Jihyun Moon, Seyeon Park, Hoyoung Lee, Jeewon Lee, Gamin Kim, Su Myeong Park, Sergio A. Lira, Andrew N. McKenzie, Hye Young Kim, Cheol Yong Choi, Yong Taik Lim, Seong Yong Park, Hye Ryun Kim, Su Hyung Park, Eui Cheol Shin, Insuk Lee, Sang Jun Ha

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22 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1393-1406
Number of pages14
JournalCancer Immunology Research
Issue number11
Publication statusPublished - 2020 Nov 1

Bibliographical note

Funding 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.

Publisher Copyright:
© 2020 American Association for Cancer Research.

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cancer Research


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