Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

Toshiro Hara; Rony Chanoch-Myers; Nathan D Mathewson; Chad Myskiw; Lyla Atta; Lillian Bussema; Stephen W Eichhorn; Alissa C Greenwald; Gabriela S Kinker; Christopher Rodman; L Nicolas Gonzalez Castro; Hiroaki Wakimoto; Orit Rozenblatt-Rosen; Xiaowei Zhuang; Jean Fan; Tony Hunter; Inder M Verma; Kai W Wucherpfennig; Aviv Regev; Mario L Suvà; Itay Tirosh

doi:10.1016/j.ccell.2021.05.002

Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

Cancer Cell. 2021 Jun 14;39(6):779-792.e11. doi: 10.1016/j.ccell.2021.05.002. Epub 2021 Jun 3.

Authors

Toshiro Hara¹, Rony Chanoch-Myers², Nathan D Mathewson³, Chad Myskiw⁴, Lyla Atta⁵, Lillian Bussema⁶, Stephen W Eichhorn⁷, Alissa C Greenwald², Gabriela S Kinker⁸, Christopher Rodman⁹, L Nicolas Gonzalez Castro¹⁰, Hiroaki Wakimoto¹¹, Orit Rozenblatt-Rosen¹², Xiaowei Zhuang⁷, Jean Fan⁵, Tony Hunter⁴, Inder M Verma⁴, Kai W Wucherpfennig³, Aviv Regev¹³, Mario L Suvà¹⁴, Itay Tirosh¹⁵

Affiliations

¹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
² Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.
³ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Cancer Immunology and Virology, Department of Microbiology and Immunobiology, Department of Neurology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
⁴ Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁵ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
⁶ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁷ Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA; Department of Chemistry and Chemical Biology, Department of Physics, Harvard University, Cambridge, MA 02138, USA.
⁸ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel; Department of Physiology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil.
⁹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁰ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology and Center for Neuro-Oncology, Brigham and Women's - Dana-Farber Cancer Center and Harvard Medical School, Boston, MA 02115, USA.
¹¹ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹² Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹³ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA 02139, USA.
¹⁴ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: suva.mario@mgh.harvard.edu.
¹⁵ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel. Electronic address: itayt@weizmann.ac.il.

Abstract

The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications.

Keywords: GBM; OSM; glioblastoma; macrophage; mesenchymal; scRNA-seq; tumor microenvironment.

Publication types

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

MeSH terms

Animals
Brain Neoplasms / genetics
Brain Neoplasms / immunology*
Brain Neoplasms / pathology*
Cells, Cultured
Cytokine Receptor gp130 / genetics
Cytokine Receptor gp130 / metabolism
Cytotoxicity, Immunologic
Gene Expression Regulation, Neoplastic
Glioblastoma / genetics
Glioblastoma / immunology*
Glioblastoma / pathology*
Humans
Leukemia Inhibitory Factor Receptor alpha Subunit / genetics
Leukemia Inhibitory Factor Receptor alpha Subunit / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Oncostatin M / metabolism
Oncostatin M Receptor beta Subunit / genetics
Oncostatin M Receptor beta Subunit / metabolism
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
T-Lymphocytes / immunology*
Tumor Microenvironment
Tumor-Associated Macrophages / immunology*
Tumor-Associated Macrophages / pathology

Substances

IL6ST protein, human
LIFR protein, human
Leukemia Inhibitory Factor Receptor alpha Subunit
OSMR protein, human
Oncostatin M Receptor beta Subunit
STAT3 Transcription Factor
STAT3 protein, human
Oncostatin M
Cytokine Receptor gp130

Abstract

Publication types

MeSH terms

Substances

Grants and funding