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Longitudinal Single Cell Profiling of Regulatory T Cells Identifies IL-33 as a Driver of Tumor Immunosuppression

88 Pages Posted: 19 Mar 2019 Publication Status: Review Complete

See all articles by Amy Li

Amy Li

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Harvard Medical School

Rebecca H. Herbst

Harvard Medical School; Masssachusetts Institute of Technology and Harvard University - Broad Institute

David Canner

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology

Jason M. Schenkel

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Brigham and Women’s Hospital - Department of Pathology

Olivia C. Smith

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Jonathan Y. Kim

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Michelle Hillman

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Arjun Bhutkar

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Michael S. Cuoco

Masssachusetts Institute of Technology and Harvard University - Broad Institute

C. Garrett Rappazzo

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Patricia Rogers

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Celeste Dang

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Livnat Jerby-Arnon

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Orit Rozenblatt-Rosen

Masssachusetts Institute of Technology and Harvard University - Broad Institute

Le Cong

Stanford University - Department of Genetics; Stanford University - Department of Pathology

Michael Birnbaum

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

Aviv Regev

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Masssachusetts Institute of Technology and Harvard University - Broad Institute; Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI)

Tyler E. Jacks

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology (MIT) - Department of Biology; Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI)

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Abstract

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 used single cell RNA-Seq to longitudinally profile conventional CD4+ T cells (Tconv) and Tregs in a genetic mouse model of lung adenocarcinoma. Tissue-infiltrating and peripheral CD4+ T cells differed, highlighting divergent pathways of activation during tumorigenesis. Longitudinal shifts in Tregs heterogeneity suggested stabilization of a specialized effector phenotype over time that had enhanced expression of the interleukin 33 receptor ST2. Tregs-specific deletion of ST2 altered lung effector Tregs diversity, increased infiltration of CD8+ T cells into tumors, and decreased tumor burden. Our study shows that ST2 plays a critical role in Tregs-mediated immunosuppression in cancer, highlighting new potential paths for therapeutic intervention.

Suggested Citation

Li, Amy and Herbst, Rebecca H. and Canner, David and Schenkel, Jason M. and Smith, Olivia C. and Kim, Jonathan Y. and Hillman, Michelle and Bhutkar, Arjun and Cuoco, Michael S. and Rappazzo, C. Garrett and Rogers, Patricia and Dang, Celeste and Jerby-Arnon, Livnat and Rozenblatt-Rosen, Orit and Cong, Le and Birnbaum, Michael and Regev, Aviv and Jacks, Tyler E., Longitudinal Single Cell Profiling of Regulatory T Cells Identifies IL-33 as a Driver of Tumor Immunosuppression (March 15, 2019). Available at SSRN: https://ssrn.com/abstract=3353223 or http://dx.doi.org/10.2139/ssrn.3353223
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Amy Li

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Rebecca H. Herbst

Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

David Canner

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Jason M. Schenkel

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Brigham and Women’s Hospital - Department of Pathology

75 Francis St.
Boston, MA 02115
United States

Olivia C. Smith

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Jonathan Y. Kim

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Michelle Hillman

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Arjun Bhutkar

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Michael S. Cuoco

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

C. Garrett Rappazzo

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Patricia Rogers

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Celeste Dang

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Livnat Jerby-Arnon

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Orit Rozenblatt-Rosen

Masssachusetts Institute of Technology and Harvard University - Broad Institute

415 Main Street
Cambridge, MA 02142
United States

Le Cong

Stanford University - Department of Genetics

Stanford, CA 94305
United States

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Michael Birnbaum

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Aviv Regev

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology ( email )

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Masssachusetts Institute of Technology and Harvard University - Broad Institute ( email )

415 Main Street
Cambridge, MA 02142
United States

Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI) ( email )

31 Ames St, 68-171
Cambridge, MA
United States

Tyler E. Jacks (Contact Author)

Massachusetts Institute of Technology (MIT) - David H. Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Massachusetts Institute of Technology (MIT) - Department of Biology ( email )

77 Massachusetts Ave
Building 68-132
Cambridge, MA 02139
United States

Massachusetts Institute of Technology (MIT) - Howard Hughes Medical Institute (HHMI) ( email )

31 Ames St, 68-171
Cambridge, MA
United States

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