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

Cell Reports (Dec 2019)

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

Affiliations

Amy Li: 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
Rebecca H. Herbst: Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
David Canner: 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
Jason M. Schenkel: 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
Olivia C. Smith: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
Jonathan Y. Kim: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
Michelle Hillman: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
Arjun Bhutkar: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
Michael S. Cuoco: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
C. Garrett Rappazzo: 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
Patricia Rogers: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
Celeste Dang: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
Livnat Jerby-Arnon: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
Orit Rozenblatt-Rosen: Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA
Le Cong: Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA
Michael Birnbaum: 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
Aviv Regev: 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; Corresponding author
Tyler Jacks: 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; Corresponding author

Journal volume & issue: Vol. 29, no. 10
pp. 2998 – 3008.e8

Abstract

Read online

Summary: Regulatory T cells (Tregs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. Tregs in human tumors span diverse transcriptional states distinct from those of peripheral Tregs, 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 Tregs in a genetically engineered mouse model of lung adenocarcinoma. In this model, interferon-responsive Tregs 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. Treg-specific deletion of ST2 alters the evolution of effector Treg diversity, increases infiltration of CD8+ T cells into tumors, and decreases tumor burden. Our study shows that ST2 plays a critical role in Treg-mediated immunosuppression in cancer, highlighting potential paths for therapeutic intervention. : Li et al. show in a genetic mouse model of lung adenocarcinoma that during tumor development regulatory T cell (Treg) diversity shifts from an interferon-responsive to a ST2-positive, Klrg1+Areg+ effector-like phenotype. Treg-specific deletion of ST2 alters Treg heterogeneity, increases tumor infiltration by CD8+ T cells, and decreases tumor burden. Keywords: regulatory T cell, autochthonous mouse model of cancer, lung adenocarcinoma, tumor immunosuppression, single cell RNA sequencing, Treg heterogeneity, interleukin-33, ST2, Il1rl1

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal