Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.
A central mechanism of tumour progression and metastasis involves the generation of an immunosuppressive 'macroenvironment' mediated in part through tumour-secreted factors. Here we demonstrate that upregulation of the Inhibitor of Differentiation 1 (Id1), in response to tumour-derived factors, such as TGFβ, is responsible for the switch from dendritic cell (DC) differentiation to myeloid-derived suppressor cell expansion during tumour progression. Genetic inactivation of Id1 largely corrects the myeloid imbalance, whereas Id1 overexpression in the absence of tumour-derived factors re-creates it. Id1 overexpression leads to systemic immunosuppression by downregulation of key molecules involved in DC differentiation and suppression of CD8 T-cell proliferation, thus promoting primary tumour growth and metastatic progression. Furthermore, advanced melanoma patients have increased plasma TGFβ levels and express higher levels of ID1 in myeloid peripheral blood cells. This study reveals a critical role for Id1 in suppressing the anti-tumour immune response during tumour progression and metastasis.
Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA.
Marianna
M
Papaspyridonos
Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA.
Irina
I
Matei
1] Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA [2] Department of Neurosurgery, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
Yujie
Y
Huang
1] Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA [2] Department of Genetics, Oncology and Human Toxicology, Faculdade de Ciência Médicas, Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008 Lisbon, Portugal.
Maria
M
do Rosario Andre
Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA.
Helene
H
Brazier-Mitouart
Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA.
Janelle C
JC
Waite
Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA.
April S
AS
Chan
Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA.
Julie
J
Kalter
Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA.
Ilyssa
I
Ramos
Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA.
Qi
Q
Wu
Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA.
Caitlin
C
Williams
1] Melanoma and Immunotherapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York City, New York 10065, USA [2] Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York City, New York 10065, USA.
Jedd D
JD
Wolchok
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York City, New York 10065, USA.
Paul B
PB
Chapman
1] Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA [2] Tumor Metastasis Laboratory, Fundación Centro Nacional de Investigaciones Oncológicas, Calle Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Hector
H
Peinado
Brigham and Women's Hospital, Department of Dermatology, Harvard Medical School, 221 Longwood Avenue EBRC, Room 513, Boston, Massachusetts 02118, USA.
Niroshana
N
Anandasabapathy
Department of Medicine, Weill Cornell Medical College and Medical Oncology/Solid Tumor Program, 1305 York Avenue, New York City, New York 10021, USA.
Allyson J
AJ
Ocean
Center for Cancer Research, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10-Hatfield CRC, Room 1-3940, Bethesda, Maryland 20892, USA.
Rosandra N
0000000285800001
RN
Kaplan
Department of Neurosurgery, Weill Cornell Medical College, 1300 York Avenue, New York City, New York 10065, USA.
Jeffrey P
JP
Greenfield
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York City, New York 10065, USA.
Jacqueline
J
Bromberg
Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA.
Dimitris
D
Skokos
1] Children's Cancer and Blood Foundation Laboratories and Departments of Pediatrics and Cell and Developmental Biology, Weill Cornell Medical College, 413 East 69th Street, New York City, New York 10021, USA [2] Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York City, New York 10065, USA.
David
D
Lyden
D000818:Animals; D002454:Cell Differentiation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000502:physiology*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology*; D009362:Neoplasm Metastasis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
D051798:Inhibitor of Differentiation Protein 1; D050835:Interferon Regulatory Factors; D016212:Transforming Growth Factor beta; D000099185:Interferon Regulatory Factor-8