To tease apart the balance between tolerance and immunity, Nirschl et al. examined an IFNγ-inducible 227 gene signature enriched in tissue-resident and migratory DCs that positively correlates with metastatic melanoma survival. One of the key induced transcripts (SOCS2) suppresses adaptive immune response, preserving tissue homeostasis, but potentially allowing tumor growth.
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. IFNgamma is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNgamma-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 IFNgamma. 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.
Author Info: (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 10
Author Info: (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, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (8) Department of Computer Science, Princeton University, Princeton, NJ 08540, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA. (9) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (10) 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. (11) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (12) Department of Dermatology, Stanford University, Stanford, CA 94305, USA. (13) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (14) Department of Genetics and Genomics Sciences Mount Sinai School of Medicine, NY, NY 10029 USA. (15) Laboratory for Investigative Dermatology, Rockefeller University. New York, NY 10065, USA. (16) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (17) Laboratory for Investigative Dermatology, Rockefeller University. New York, NY 10065, USA. (18) Laboratory for Investigative Dermatology, Rockefeller University. New York, NY 10065, USA. (19) Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (20) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02458, USA. (21) Department of Computer Science, Princeton University, Princeton, NJ 08540, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA. (22) Laboratory for Investigative Dermatology, Rockefeller University. New York, NY 10065, USA. (23) Department of Dermatology, Stanford University, Stanford, CA 94305, USA. (24) 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. (25) 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. (26) 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. (27) 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. (28) 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. (29) 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.
