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.We thank the members of our laboratories for their helpful discussions. We thank Dr. Sergei Rudchenko and Mihaela Barbu-Stevanovic at the Hospital for Special Surgery Fannie E. Rippel Foundation Flow Cytometry Core Facility for expert cell sorting. Our work was supported by grants from the UK-US Fulbright Commission (M.P.), the Garrett B. Smith Foundation (M.P.), 5th District AHEPA Cancer Research Foundation (M.P. and D.L.), the Children's Cancer and Blood Foundation (D.L.), The Hartwell Foundation (D.L.), The Manning Foundation (D.L.), Pediatric Oncology Experimental Therapeutics Investigator's Consortium (D.L.), Stavros S. Niarchos Foundation (D.L.), Champalimaud Foundation (D.L.), The Nancy C. and Daniel P. Paduano Foundation (D.L. and H.P.), The Mary Kay Foundation (D.L.), The Malcolm Hewitt Wiener Foundation (D.L.), National Foundation for Cancer Research (D.L.), Susan G. Komen for the Cure (D.L.), Luso-American Development Foundation (M.d.R.A.), American Portuguese Biomedical Research Fund (M.d.R.A.) and D.L. Fundacao para a Ciencia e a Tecnologia (D.L.), Beth Tortolani Foundation (D.L. and J.B.) and Theodore A Rapp Foundation (D.L.).S