TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state

Satoru Matsuda; Ajinkya Revandkar; Taronish D. Dubash; Arvind Ravi; Ben S. Wittner; Maoxuan Lin; Robert Morris; Risa Burr; Hongshan Guo; Karsen Seeger; Annamaria Szabolcs; Dante Che; Linda Nieman; Gad A. Getz; David T. Ting; Michael S. Lawrence; Justin Gainor; Daniel A. Haber; Shyamala Maheswaran

Cell Reports (Mar 2023)

TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state

Satoru Matsuda,
Ajinkya Revandkar,
Taronish D. Dubash,
Arvind Ravi,
Ben S. Wittner,
Maoxuan Lin,
Robert Morris,
Risa Burr,
Hongshan Guo,
Karsen Seeger,
Annamaria Szabolcs,
Dante Che,
Linda Nieman,
Gad A. Getz,
David T. Ting,
Michael S. Lawrence,
Justin Gainor,
Daniel A. Haber,
Shyamala Maheswaran

Affiliations

Satoru Matsuda: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Ajinkya Revandkar: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Taronish D. Dubash: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Arvind Ravi: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA 02139, USA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Ben S. Wittner: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Maoxuan Lin: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Robert Morris: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Risa Burr: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Hongshan Guo: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Karsen Seeger: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Annamaria Szabolcs: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Dante Che: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Linda Nieman: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Gad A. Getz: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
David T. Ting: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Michael S. Lawrence: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Justin Gainor: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding author
Daniel A. Haber: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Howard Hughes Medical Institute, Bethesda, MD 20815, USA; Corresponding author
Shyamala Maheswaran: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 3
p. 112129

Abstract

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Summary: TGF-β induces senescence in embryonic tissues. Whether TGF-β in the hypoxic tumor microenvironment (TME) induces senescence in cancer and how the ensuing senescence-associated secretory phenotype (SASP) remodels the cellular TME to influence immune checkpoint inhibitor (ICI) responses are unknown. We show that TGF-β induces a deeper senescent state under hypoxia than under normoxia; deep senescence correlates with the degree of E2F suppression and is marked by multinucleation, reduced reentry into proliferation, and a distinct 14-gene SASP. Suppressing TGF-β signaling in tumors in an immunocompetent mouse lung cancer model abrogates endogenous senescent cells and suppresses the 14-gene SASP and immune infiltration. Untreated human lung cancers with a high 14-gene SASP display immunosuppressive immune infiltration. In a lung cancer clinical trial of ICIs, elevated 14-gene SASP is associated with increased senescence, TGF-β and hypoxia signaling, and poor progression-free survival. Thus, TME-induced senescence may represent a naturally occurring state in cancer, contributing to an immune-suppressive phenotype associated with immune therapy resistance.

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

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