IL-33 Signaling Alters Regulatory T Cell Diversity in Support of Tumor Development

Amy Li; Rebecca H Herbst; David Canner; Jason M Schenkel; Olivia C Smith; Jonathan Y Kim; Michelle Hillman; Arjun Bhutkar; Michael S Cuoco; C Garrett Rappazzo; Patricia Rogers; Celeste Dang; Livnat Jerby-Arnon; Orit Rozenblatt-Rosen; Le Cong; Michael Birnbaum; Aviv Regev; Tyler Jacks

doi:10.1016/j.celrep.2019.10.120

IL-33 Signaling Alters Regulatory T Cell Diversity in Support of Tumor Development

Cell Rep. 2019 Dec 3;29(10):2998-3008.e8. doi: 10.1016/j.celrep.2019.10.120.

Authors

Amy Li¹, Rebecca H Herbst², David Canner³, Jason M Schenkel⁴, Olivia C Smith⁵, Jonathan Y Kim⁵, Michelle Hillman⁵, Arjun Bhutkar⁵, Michael S Cuoco⁶, C Garrett Rappazzo⁷, Patricia Rogers⁶, Celeste Dang⁵, Livnat Jerby-Arnon⁶, Orit Rozenblatt-Rosen⁶, Le Cong⁸, Michael Birnbaum⁷, Aviv Regev⁹, Tyler Jacks¹⁰

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA.
² Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
⁶ Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
⁷ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, 21 Ames Street, Cambridge, MA 02142, USA.
⁸ Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
⁹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
¹⁰ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].

Abstract

Regulatory T cells (T_regs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. T_regs in human tumors span diverse transcriptional states distinct from those of peripheral T_regs, but their contribution to tumor development remains unknown. Here, we use single-cell RNA sequencing (RNA-seq) to longitudinally profile dynamic shifts in the distribution of T_regs in a genetically engineered mouse model of lung adenocarcinoma. In this model, interferon-responsive T_regs are more prevalent early in tumor development, whereas a specialized effector phenotype characterized by enhanced expression of the interleukin-33 receptor ST2 is predominant in advanced disease. T_reg-specific deletion of ST2 alters the evolution of effector T_reg diversity, increases infiltration of CD8⁺ T cells into tumors, and decreases tumor burden. Our study shows that ST2 plays a critical role in T_reg-mediated immunosuppression in cancer, highlighting potential paths for therapeutic intervention.

Keywords: Il1rl1; ST2; Treg heterogeneity; autochthonous mouse model of cancer; interleukin-33; lung adenocarcinoma; regulatory T cell; single cell RNA sequencing; tumor immunosuppression.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / immunology
Female
Immune Tolerance / immunology
Immunosuppression Therapy / methods
Interleukin-33 / immunology*
Male
Mice
Mice, Inbred C57BL
Neoplasms / immunology
Signal Transduction / immunology*
T-Lymphocytes, Regulatory / immunology*
Tumor Microenvironment / immunology

Substances

Il33 protein, mouse
Interleukin-33

Abstract

Publication types

MeSH terms

Substances

Grants and funding