Identification of an Immature Subset of PMN-MDSC Correlated to Response to Checkpoint Inhibitor Therapy in Patients with Metastatic Melanoma.

Françoise Gondois-Rey,Magali Paul,Sarah Bourass,Daniel Olive,Florence Alcaraz,Jilliana Monnier,Caroline Gaudy-Marqueste,Jean-Jacques Grob,Nausicaa Malissen,Pierre Van Der Bruggen,Annika M Bruger

doi:10.3390/cancers13061362

Abstract

Simple SummaryPolymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs) have been associated to bad prognosis and resistance to immune checkpoint inhibitor (ICI) therapy in metastatic melanoma (MM). In this study, we describe an immature subset of PMN-MDSCs capable of a high cytotoxicity against T cells mediated by a MAC-1 interaction, characterized by the absence of expression of the signal regulatory protein alpha. This subset is increased in patients responding to ICI therapy. Although the processes involving these cells in vivo are unknown, low-density CD15+SIRPα− cells might constitute a useful biomarker to monitor clinical response in MM patients.PMN-MDSCs support tumor progression and resistance to ICI therapy through their suppressive functions but their heterogeneity limits their use as biomarkers in cancer. Our aim was to investigate the phenotypic and functional subsets of PMN-MDSCs to identify biomarkers of response to ICI therapy. We isolated low-density CD15+ PMNs from patients with metastatic melanoma and assessed their immune-suppressive capacities. Expression of CD10 and CD16 was used to identify mature and immature subsets and correlate them to inhibition of T cell proliferation or direct cytotoxicity. Frequencies of the PMN-MDSCs subsets were next correlated to the radiological response of 36 patients receiving ICI therapy. Mature activated cells constituted the major population of PMN-MDSCs. They were found in a higher proportion in the pre-treatment blood of patients non responders to ICI. A subset of immature cells characterized by intermediate levels of CD10 and CD16, the absence of expression of SIRPα and a strong direct cytotoxicity to T cells was increased in patients responding to ICI. The paradoxical expansion of such cells during ICI therapy suggests a role of PMNs in the inflammatory events associated to efficient ICI therapy and the usefulness of their monitoring in patients care.

Highlights

Myeloid-derived suppressive cells (MDSCs) have become increasingly attractive for the development of immune-based therapies against cancer, as both potential biomarkers to monitor treatment response and targets to counteract immune suppression and resistance to treatment
CD10+ and CD10– subsets are further gated in the PMN-MDSCs. (b) Inhibition of T cell proliferation in co-culture with high-density PMNs from healthy donor
Since MAC-1 is necessary for trogocytosis we investigated whether this mechanism was involved in the cytotoxicity of PMN-MDSCs by analyzing the expression of the Celltrace T cells dye in PMN-MDSCs after overnight co-culture (Figure 3c)

Summary

Introduction

Myeloid-derived suppressive cells (MDSCs) have become increasingly attractive for the development of immune-based therapies against cancer, as both potential biomarkers to monitor treatment response and targets to counteract immune suppression and resistance to treatment. PMN-MDSCs are commonly defined by their low-density in Ficoll gradients while normal PMNs are separated from peripheral blood mononuclear cells (PBMCs) by their high-density. Low-density PMNs are expanded in cancer [9,10] and their rapid decrease under efficient therapy suggest that they may constitute interesting biomarkers [7]. Lowdensity PMNs share many attributes with high-density PMNs including high granularity and the expression of granulocyte surface markers [11]. They are heterogeneous and contain populations expressing combinations of markers that suggest various stages of maturation or activation [12]. Cells isolated as low-density PMN-MDSCs could include activated PMNs, which are commonly expanded in cancer [13]

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