Polarization and reprogramming of myeloid-derived suppressor cells

Abstract

Myeloid-derived suppressor cells (MDSC) have recently emerged as one of the central regulators of the immune system. In recent years, interest in understanding MDSC biology and applying MDSC for therapeutic purpose has exploded exponentially. Despite recent progress in MDSC biology, the mechanisms underlying MDSC development from expansion and activation to polarization in different diseases remain poorly understood. More recent studies have demonstrated that two MDSC subsets, M (monocytic)-MDSC and G (granulocytic)-MDSC, are able to polarize from a classically activated phenotype (M1) to an alternatively activated one (M2), or vice versa, in tumor-bearing mice. This phenotypic polarization affects MDSC function and disease progression. In this article, we summarize and discuss polarization, mechanism and therapeutic potential of MDSC. An emphasis is placed on the emerging concept of reprogramming MDSC polarization as a therapeutic strategy.

Figure 1

Novel vista on the use of reprogramming MDSC polarization as a novel therapeutic approach to treat cancers and other disorders. (A) ‘Yin-Yang’ balance in M1/M2 polarization of MDSC may relate to disease and health, and can be harnessed for the treatment of various diseases. Polarization of MDSC toward M1 phenotype can inhibit tumor growth, whereas undesirable immune responses, e.g. autoimmunity, transplant rejection and graft-versus-host diseases (GVHD) can be suppressed through the use of M2-polarized MDSC as a cell-based tolerogenic therapy. M2-polarized MDSC are characterized by their suppressive effect, anti-inflammatory activity and immune tolerance. In contrast, M1 cells possess pro-inflammatory and immunostimulatory activities. (B) MDSC-polarizing compounds can convert pro-tumoral cells M2 MDSC into tumoricidal M1 cells. In this case, TGF-β inhibitor, SM16, acts to inhibit its kinase activity and, in turn, skews G2 G-MDSC to G1 G-MDSC. SHP1 inhibitor, NSC87877, can shift M2 M-MDSC to M1 M-MDSC. Both compounds suppress tumor growth. Overall, control of M1/M2 MDSC reprogramming has emerged as a novel approach to treat cancers and other diseases.