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
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
