Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.
Marianna PapaspyridonosIrina MateiYujie HuangMaria do Rosario AndreHelene Brazier-MitouartJanelle C WaiteApril S ChanJulie KalterIlyssa RamosQi WuCaitlin WilliamsJedd D WolchokPaul B ChapmanHector PeinadoNiroshana AnandasabapathyAllyson J OceanRosandra N KaplanJeffrey P GreenfieldJacqueline BrombergDimitris SkokosDavid LydenPublished in: Nature communications (2015)
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.
Keyphrases
- dendritic cells
- cell proliferation
- immune response
- peripheral blood
- signaling pathway
- small cell lung cancer
- acute myeloid leukemia
- bone marrow
- single cell
- transcription factor
- gene expression
- squamous cell carcinoma
- ejection fraction
- induced apoptosis
- regulatory t cells
- dna methylation
- newly diagnosed
- cell cycle
- prognostic factors
- transforming growth factor
- genome wide
- epithelial mesenchymal transition