Myeloid derived-suppressor cells: their role in cancer and obesity

Abstract

Myeloid-derived suppressor cells (MDSC) are present in most individuals with cancer where they inhibit adaptive and innate antitumor immunity and are an obstacle to cancer immunotherapies. Chronic inflammation is characteristic of adipose tissue and is a risk factor for the onset and progression of cancer in obese individuals. Because MDSC accumulate in response to inflammation, it has been hypothesized that one of the mechanisms by which obesity promotes malignancy is through the induction of MDSC. This article reviews the data supporting this hypothesis, the role of leptin and fatty acid metabolism in the induction of MDSC, and the surprising finding that although MDSC promote tumor progression, they are protective against some of the metabolic dysfunction associated with obesity.

Figure 1

MDSC development, accumulation, suppressive activity, and survival are regulated by a complex network of transcription factors, cytokines, and non-cytokine immune regulatory factors produced by tumor cells and host cells. MDSC originate from the common myeloid progenitor (CMP) cell in the bone marrow (also in the spleen of mice) during myelopoiesis. There are two subtypes of MDSC: mononuclear (M-MDSC) and polymorphonuclear or granulocytice MDSC (PMN-MDSC). Tumor cells and/or host cells in the periphery produce cytokines and other factors that drive MDSC differentiation. From the bone marrow (and spleen of mice), MDSC circulate in the blood and home to sites of inflammation and to solid tumors. Within an inflammatory milieu such as the tumor microenvironment, a variety of factors promote MDSC suppressive activity. The survival of MDSC is facilitated by some of the same conditions and mediators that regulate MDSC accumulation, as well as genes that limit apoptosis. A variety of cells including tumor cells, adipocytes, macrophages, mast cells, dendritic cells, and cancer-associated fibroblasts produce molecules that regulate MDSC.

Figure 2

Adipose tissue drives the accumulation of MDSC which protect against some obesity-induced metabolic dysfunction, but promote tumor progression. The chronic inflammatory milieu of adipose tissue induces the accumulation of PMN-MDSC and M-MDSC. The induced MDSC reduce elevated blood glucose levels insulin tolerance associated with obesity, but simultaneously increase the accumulation of fat cells. Obesity-induced MDSC have enhanced potency and promote tumor growth by suppressing tumor-reactive T cells and preventing the entry of activated T cells into the tumor microenvironment.

Figure 3

Obesity-associated molecules increase the accumulation and potency of MDSC through at least three independent mechanisms. (a) Chronic inflammation in adipose tissue induces the over-production of leptin which drives the accumulation of MDSC in blood and in solid tumor. Elevated levels of MDSC decrease leptin production resulting in feedback, feed-forward regulation of both leptin and MDSC. Leptin-induced MDSC in the tumor microenvironment have elevated expression of PDL1, which may contribute to their increased suppressive activity. (b) PUFAs increase the differentiation of MDSC from bone marrow progenitor cells and enhance MDSC suppressive activity by activating STAT3 which increases the p47 subunit of NOX2. ROS are upregulated resulting in an increase in peroxynitrite which subsequently causes anergy of activated T cells and impairs activation of naïve T cells. (c) G-CSF and GM-CSF generated within the tumor microenvironment increase PMN-MDSC and M-MDSC uptake of lipids by upregulating MDSC synthesis of the lipid receptors CD36 and Msr1. Fatty acid oxidative enzymes are also upregulated in the MDSC, resulting in increased suppressive activity due to increased arginase I and peroxynitrite.