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Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

ABSTRACT: 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 TGF?, 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 TGF? 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.

SUBMITTER: Papaspyridonos M

PROVIDER: S-EPMC4423225 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

Papaspyridonos Marianna M Matei Irina I Huang Yujie Y do Rosario Andre Maria M Brazier-Mitouart Helene H Waite Janelle C JC Chan April S AS Kalter Julie J Ramos Ilyssa I Wu Qi Q Williams Caitlin C Wolchok Jedd D JD Chapman Paul B PB Peinado Hector H Anandasabapathy Niroshana N Ocean Allyson J AJ Kaplan Rosandra N RN Greenfield Jeffrey P JP Bromberg Jacqueline J Skokos Dimitris D Lyden David D

Nature communications 20150429

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 th ...[more]

PMID: 25924227

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Project description:Background & aimsThe mechanism underlying resistance to immunotherapy involves engagement of immune checkpoint pathways. The transcriptional and epigenetic processes of checkpoint molecules, however, have not been well investigated. We thus studied whether the transcription factor myeloid zinc finger 1 (MZF1) may promote resistance to immunotherapy in hepatocellular carcinoma (HCC).MethodsSingle-cell RNA-sequencing was performed to study the correlation between MZF1 and tumour microenvironment features in six patients with HCC. Combined immunohistochemistry and multi-immunofluorescence analyses were performed for verification. Ectopic expression of MZF1 was used in both orthotopic and genetically engineered hydrodynamic mouse HCC models for in vivo experiments. Proteome analysis, including protein degradation assays, ubiquitination assays, and co-immunoprecipitation assays, revealed the function of MZF1 in immune checkpoint pathways.ResultsSingle-cell RNA-sequencing suggested an immunosuppressive environment and a strong correlation with the immune checkpoint programmed death ligand 1 (PD-L1) in MZF1-overexpressing tumours. Analyses of 163 HCC samples demonstrated that MZF1 expression in HCC cells is associated with decreased T-cell infiltration. In vivo experiments showed that ectopic MZF1 expression in HCC cells impairs T-cell recruitment, resulting in resistance to immune checkpoint blockade. Mechanistically, MZF1 accelerated PD-L1 ubiquitination by binding to the cyclin-dependent kinase 4 (CDK4) activation site, while a direct bond between CDK4 and MZF1 led to increased MZF1 expression.ConclusionsMZF1 promotes PD-L1 ubiquitination via CDK4 and possibly MZF1. Inhibition of CDK4 can therefore restore PD-L1 expression and may be a potential strategy for combination with anti-PD-L1 antibodies.Impact and implicationsResistance to immune checkpoint blockade with anti-programmed death ligand 1 (PD-L1) antibody therapy is attributed to oncogenic alterations of tumour cells, however, effective countermeasures are yet to be established. Here, we report that the transcription factor myeloid zinc finger 1 (MZF1) can bind to the cyclin-dependent kinase 4 (CDK4) activation site and accelerate PD-L1 ubiquitination. A CDK4 inhibitor therefore enhances anti-PD-L1 antibody efficacy by blocking MZF1 signalling. This indicates a potential benefit of combining CDK4 inhibitors and anti-PD-L1 antibodies for the treatment of advanced HCC.

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Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

Publications

Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation.

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