High expression of ID1 in monocytes is strongly associated with phenotypic and functional MDSC markers in advanced melanoma

Jeroen Melief,Felix-Lennart Fennemann,Maria Wolodarski,Johan Hansson,Rolf Kiessling,Yago Pico De Coaña,Roeltje Maas

doi:10.1007/s00262-019-02476-9

Abstract

The efficacy of immunotherapies for malignant melanoma is severely hampered by local and systemic immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Inhibitor of differentiation 1 (ID1) is a transcriptional regulator that was shown to be centrally involved in the induction of immunosuppressive properties in myeloid cells in mice, while it was overexpressed in CD11b+ cells in the blood of late-stage melanoma patients. Therefore, we comprehensively assessed ID1 expression in PBMC from stage III and IV melanoma patients, and studied ID1 regulation in models for human monocyte differentiation towards monocyte-derived dendritic cells. A highly significant elevation of ID1 was observed in CD33+CD11b+CD14+HLA-DRlow monocytic MDSC in the blood of melanoma patients compared to their HLA-DRhigh counterparts, while expression of ID1 correlated positively with established MDSC markers S100A8/9 and iNOS. Moreover, expression of ID1 in monocytes significantly decreased in PBMC samples taken after surgical removal of melanoma metastases, compared to those taken before surgery. Finally, maturation of monocyte-derived DC coincided with a significant downregulation of ID1. Together, these data indicate that increased ID1 expression is strongly associated with expression of phenotypic and immunosuppressive markers of monocytic MDSC, while downregulation is associated with a more immunogenic myeloid phenotype. As such, ID1 may be an additional phenotypic marker for monocytic MDSC. Investigation of ID1 as a pharmacodynamic biomarker or its use as a target for modulating MDSC is warranted.

Highlights

Current immunotherapies for malignant melanoma mostly aim to promote T-cell-mediated immune responses against the tumor, for example via checkpoint blockade, adoptive transfer of T cells, or vaccination strategies
We studied inhibitor of differentiation 1 (ID1) expression in parallel with more established myeloid-derived suppressor cells (MDSC) markers, to evaluate to what extent ID1 can serve as an accurate marker to distinguish HLA-DRlow monocytic MDSC from normal HLADRhigh monocytes in humans
We started out by studying levels CD33+CD11b+CD14+ cells for expression of ID1 in relation to markers commonly used for characterization of monocytic MDSC: HLA-DR, inducible nitric oxide synthase 2 (iNOS), and S100A8/9

Summary

Introduction

Current immunotherapies for malignant melanoma mostly aim to promote T-cell-mediated immune responses against the tumor, for example via checkpoint blockade, adoptive transfer of T cells, or vaccination strategies. Even though these approaches have improved overall survival rates in melanoma, many immunotherapies still display limited efficacy on their own [1]. One very good example in this respect is blockade of prostaglandin E2 (PGE2) secretion, which was shown to prevent induction of an MDSC-like phenotype in human monocytes [9] It was found in melanoma mouse models that tumor cells through TGF-β production can promote MDSC formation by induction of the transcriptional regulator called inhibitor of differentiation 1 (ID1) [10]. Increased ID1 expression in tumors has been associated with poor outcome in breast, esophageal, and pancreatic cancers [11,12,13]

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