IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment

Christopher J Nirschl; Mayte Suárez-Fariñas; Benjamin Izar; Sanjay Prakadan; Ruth Dannenfelser; Itay Tirosh; Yong Liu; Qian Zhu; K Sanjana P Devi; Shaina L Carroll; David Chau; Melika Rezaee; Tae-Gyun Kim; Ruiqi Huang; Judilyn Fuentes-Duculan; George X Song-Zhao; Nicholas Gulati; Michelle A Lowes; Sandra L King; Francisco J Quintana; Young-Suk Lee; James G Krueger; Kavita Y Sarin; Charles H Yoon; Levi Garraway; Aviv Regev; Alex K Shalek; Olga Troyanskaya; Niroshana Anandasabapathy

doi:10.1016/j.cell.2017.06.016

IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment

Cell. 2017 Jun 29;170(1):127-141.e15. doi: 10.1016/j.cell.2017.06.016.

Authors

Christopher J Nirschl¹, Mayte Suárez-Fariñas², Benjamin Izar³, Sanjay Prakadan⁴, Ruth Dannenfelser⁵, Itay Tirosh⁶, Yong Liu¹, Qian Zhu⁵, K Sanjana P Devi¹, Shaina L Carroll⁴, David Chau¹, Melika Rezaee⁷, Tae-Gyun Kim¹, Ruiqi Huang⁸, Judilyn Fuentes-Duculan⁹, George X Song-Zhao¹, Nicholas Gulati⁹, Michelle A Lowes⁹, Sandra L King¹, Francisco J Quintana¹⁰, Young-Suk Lee⁵, James G Krueger⁹, Kavita Y Sarin⁷, Charles H Yoon¹¹, Levi Garraway¹², Aviv Regev¹³, Alex K Shalek¹⁴, Olga Troyanskaya¹⁵, Niroshana Anandasabapathy¹⁶

Affiliations

¹ Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Department of Dermatology, Mount Sinai School of Medicine, NY, NY 10029, USA; Department of Genetics and Genomics Sciences Mount Sinai School of Medicine, NY, NY 10029 USA; Population Health Science and Policy, Mount Sinai School of Medicine, NY, NY 10029, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science and Department of Chemistry, MIT, Cambridge, MA 02139, USA; Ragon Institute of MIT, Harvard, and MGH, Cambridge, MA 02139, USA.
⁵ Department of Computer Science, Princeton University, Princeton, NJ 08540, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Department of Dermatology, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Genetics and Genomics Sciences Mount Sinai School of Medicine, NY, NY 10029 USA.
⁹ Laboratory for Investigative Dermatology, Rockefeller University. New York, NY 10065, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02458, USA.
¹¹ Department of Surgical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Surgical Oncology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Biology and Koch Institute, MIT, Boston, MA 02142, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Medical Engineering and Science and Department of Chemistry, MIT, Cambridge, MA 02139, USA; Ragon Institute of MIT, Harvard, and MGH, Cambridge, MA 02139, USA; Division of Health Science & Technology, Harvard Medical School, Cambridge, MA 02139, USA; Department of Immunology, Massachusetts General Hospital, Boston, MA 02115, USA.
¹⁵ Department of Computer Science, Princeton University, Princeton, NJ 08540, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA; Simons Center for Data Analysis, Simons Foundation, New York, NY 10010, USA.
¹⁶ Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cancer Immunology and Melanoma, Harvard Cancer Center, Dana Farber Cancer Center, Boston, MA 02215, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: nanandasabapathy@partners.org.

Abstract

Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.

Keywords: IFNγ; dendritic cells; differentiation; homeostasis; immunotherapy; melanoma; suppressor-of-cytokine-signaling 2 (SOCS2); tissue mononuclear phagocytes; tolerance; tumor microenvironment.

MeSH terms

Animals
Cell Differentiation
Dendritic Cells / immunology
Homeostasis
Humans
Interferon-gamma / immunology*
Melanoma / genetics
Melanoma / immunology*
Melanoma / pathology
Mice
Monocytes / immunology*
Monocytes / pathology
Neoplasm Metastasis / pathology*
Sequence Analysis, RNA
Single-Cell Analysis
Skin Neoplasms / genetics
Skin Neoplasms / immunology*
Skin Neoplasms / pathology
Suppressor of Cytokine Signaling Proteins / metabolism*
Transcriptome
Tumor Microenvironment*

Substances

IFNG protein, human
SOCS2 protein, human
Suppressor of Cytokine Signaling Proteins
Interferon-gamma

Abstract

MeSH terms

Substances

Grants and funding