Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their Environment

Abstract

Myeloid-derived suppressor cells (MDSC) are a diverse population of immature myeloid cells that have potent immune-suppressive activity. Studies in both mice and humans have demonstrated that MDSC accumulate in most individuals with cancer, where they promote tumor progression, inhibit antitumor immunity, and are an obstacle to many cancer immunotherapies. As a result, there has been intense interest in understanding the mechanisms and in situ conditions that regulate and sustain MDSC, and the mechanisms MDSC use to promote tumor progression. This article reviews the characterization of MDSC and how they are distinguished from neutrophils, describes the suppressive mechanisms used by MDSC to mediate their effects, and explains the role of proinflammatory mediators and the tumor microenvironment in driving MDSC accumulation, suppressive potency, and survival.

Figure 1. Phenotype and immune suppressive functions of mouse and human monocytic (M-MDSC) and polymorphonuclear (PMN-MDSC) MDSC

Lin⁻ indicates cells are negative for CD3, CD19, CD20, and CD56.

Figure 2. Cytokines, immune regulatory molecules, and transcription factors control the development, accumulation, suppressive potency, and survival of MDSC

Growth factors, hormones, and transcription factors that regulate myelopoiesis induce the expansion of MDSC in bone marrow. Within the pro-inflammatory tumor microenvironment a variety of cytokines and non-cytokine regulatory proteins are produced by tumor cells and tumor-infiltrating host cells (e.g. DCs, lymphocytes, macrophages, mast cells, and fibroblasts) and increase MDSC suppressive potency by activating transcription factors and signal transduction pathways in MDSC. Survival of MDSC is mediated by many of the same factors/conditions that induce the accumulation of MDSC plus cell surface receptors and genes that prevent/limit apoptosis.

Figure 3. MDSC use a variety of immune and non-immune mechanisms to promote tumor progression, but have beneficial effects in other settings

In individuals with cancer, MDSC inhibit adaptive antitumor immunity by suppressing CD4⁺ and CD8⁺ T cell activation and function, and by driving and recruiting T regulatory cells. They inhibit innate immunity by polarizing macrophages towards a type 2 tumor-promoting phenotype and by inhibiting NK-mediated cytotoxicity. MDSC also promote cancer cell stemness and facilitate angiogenesis and drive tumor invasion and metastasis. Beneficial effects of MDSC include their lowering of blood glucose levels and reduction of insulin tolerance in obese individuals, and their maintenance of maternal-fetal tolerance and embryo implantation during pregnancy.