Using several murine tumor models, Son and Cho et al. showed accumulation of intratumoral Tregs with elevated expression of immune checkpoint molecules and of genes related to immune suppression, proliferation, chemotaxis and apoptosis, consistent with data for intratumoral Tregs from patients with NSCLC. ST2, an IL-1 receptor family member, was increased on murine (and NSCLC) intratumoral Tregs. ST2-ligand IL-33 levels increased intratumorally, induced accumulation and clonal expansion of intratumoral ST2+ Tregs, and enhanced tumor progression. Genetic deletion of ST2 from Tregs or treatment with an anti-ST2 antibody delayed tumor growth.
Contributed by Paula Hochman
ABSTRACT: Regulatory T cells (Tregs) are enriched in the tumor microenvironment (TME) and suppress antitumor immunity. However, the molecular mechanism underlying the accumulation of Tregs in the TME are poorly understood. In various tumor models, tumor-infiltrating Tregs were highly enriched in TME and had significantly higher expression 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 to tumor-infiltrating CD4+Foxp3- conventional T cells or splenic Tregs from the same tumor-bearing mice. Single-cell RNA sequencing and T-cell receptor sequencing also revealed active proliferation of tumor infiltrating Tregs by clonal expansion. One of these genes, ST2, an interleukin-33 (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.
Author Info: (1) Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University. (2) Department of Biotechnology, Yonsei University. (3) Department of Biochemistry, Yons
Author Info: (1) Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University. (2) Department of Biotechnology, Yonsei University. (3) Department of Biochemistry, Yonsei University. (4) Yonsei University. (5) Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, Korea. (6) Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology. (7) Biomedical Science and Engineering Interdisciplinary Program, KAIST. (8) yonsei cancer center, Yonsei University College of Medicine. (9) yonsei cancer center, Yonsei University College of Medicine. (10) Immunology Institute, Icahn School of Medicine at Mount Sinai. (11) MRC. (12) Biomedical Sciences, Seoul National University. (13) Department of Biological Sciences, Sungkyunkwan University. (14) Sungkyunkwan University, South Korea. (15) Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea. (16) Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine. (17) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology. (18) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology. (19) Biotechnology, Yonsei University. (20) Department of Biochemistry, Yonsei University sjha@yonsei.ac.kr.
