Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer

Abstract

Myeloid-derived suppressor cells (MDSCs) play an important role in immune suppression and accumulate under pathologic conditions such as cancer and chronic inflammation. They comprise a heterogeneous population of immature myeloid cells that exert their immunosuppressive function via a variety of mechanisms. Immunoglobulin-like transcript 3 (ILT3) is a receptor containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) that can be expressed on antigen-presenting cells and is an important regulator of dendritic cell tolerance. ILT3 exists in a membrane-bound and a soluble form and can interact with a yet unidentified ligand on T cells and thereby induce T-cell anergy, regulatory T cells, or T suppressor cells. In this study, we analyzed freshly isolated peripheral blood mononuclear cells (PBMCs) of 105 patients with non-small cell lung cancer and 20 healthy controls and demonstrated for the first time that ILT3 is expressed on MDSCs. We show that increased levels of circulating MDSCs correlate with reduced survival. On the basis of ILT3 cell surface expression, an ILT3^low and ILT3^high population of polymorphonuclear (PMN)-MDSCs could be distinguished. Interestingly, in line with the immunosuppressive function of ILT3 on dendritic cells, patients with an increased proportion of PMN-MDSCs and an increased fraction of the ILT3^high subset had a shorter median survival than patients with elevated PMN-MDSC and a smaller ILT3^high fraction. No correlation between the ILT3^high subset and other immune variables was found. ILT3 expressed on MDSCs might reflect a previously unknown mechanism by which this cell population induces immune suppression and could therefore be an attractive target for immune intervention.

Keywords:

• CD85k
• immunoglobulin-like transcript 3
• immune suppression
• LILRB4
• LIR-5
• myeloid-derived suppressor cells
• non-small cell lung cancer
• overall survival

Abbreviations:

• APC, antigen-presenting cell
• DC, dendritic cell
• ELISA, enzyme-linked immunosorbent assay
• HC, healthy control
• ILT3, immunoglobulin-like transcript 3
• MDSC, myeloid-derived suppressor cell
• MFI, mean fluorescence intensity
• MO-MDSC, monocytic MDSC
• NFκB, nuclear factor κB
• NSCLC, non-small cell lung carcinoma
• PBMC, peripheral blood mononuclear cell
• PMN-MDSC, polymorphonuclear MDSC
• sILT3, soluble ILT3
• Treg, regulatory T cell
• Ts, T suppressor cell

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.