Suppression of T cells by myeloid-derived suppressor cells in cancer

Abstract

Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their immunosuppression. Elevated levels of certain soluble cytokines in tumor microenvironment, such as IL-6 and IL-10, contribute to the recruitment and accumulation of tumor-associated MDSCs. In turn, MDSCs secret IL-6 and IL-10 and form a positive self-feedback to promote self-expansion. MDSCs also release other soluble cytokines such as TGF-β and chemokines to exert their suppressive function by induction of regulatory T cells. Exhaustion of some amino acids by MDSCs with many secretory enzymes or membrane transporters as well as their metabolites leads to blockage of T cells development. The interaction of membrane molecules on MDSCs and T cells leads inactivation and apoptosis of T cells. There may be one or some dominant mechanism(s) by which MDSCs impair the immune system in different tumor microenvironment. Thus, it is important to identify the subpopulations of MDSCs and clarify the dominant mechanism(s) through which MDSCs inhibit antitumor immunity in order to establish a more individual immunotherapy by eliminating MDSCs-mediated suppression. Currently studies concentrated on therapeutic strategies targeting MDSCs have obtained promising results. However, more studies are needed to demonstrate their clinical safety and efficacy.

Introduction

Myeloid-derived suppressor cells (MDSCs) were first detected in mouse models bearing human tumors [1] before they were identified in patients with head and neck squamous cancer several years later [2]. Actually, MDSCs are a heterogeneous population of immature myeloid cells including granulocytes, macrophages and dendritic cells [3], [4], which display potent inhibitory effect on immunity and result in immune evasion. Commonly, murine MDSCs are characterized by the expression of Gr-1 and CD11b and represent approximately 2–4% of all nucleated splenocytes, but can increase up to 50% in tumor bearing mice [5], [6]. The equivalent MDSCs in humans are usually positive for both CD11b and CD33 or express the CD33 but lack the expression of the major histocompatibility complex (MHC) class II molecule HLA-DR. They account for less than 0.5% of peripheral blood mononuclear cells in healthy individuals, but can increase more than 10 folds in circulation of cancer patients [7], [8], [9], [10]. There are two main MDSC subtypes both in mice and humans, polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC), in which PMN -MDSCs represent the major subset of circulating MDSC [11]. However, the specific markers for MDSC subsets, especially in humans, are vague until now and MDSCs are primarily identified by their suppressive function.

Nowadays, it has been demonstrated that MDSCs are associated with poor prognosis in cancer patients [12], promote tumor angiogenesis [13], and inhibit both innate and adaptive immunity against tumors [14]. Depletion of MDSCs was reported to enhance the antigen presenting cell activity and increase the frequency and activity of the NK and T cell effectors in murine models of lung cancer [15]. Many studies have focused on the cancer-associated immune-suppression mechanisms mediated by MDSCs [16], [17], in which inactivation of T cells is underscored. T cells represent a key effector arm of the immune system that is required for cancer control. Dysfunction of T cells fails to response to transformed cells, thus tumor-surveillance is impaired. Therefore, this review aims to introduce the underlying molecular mechanisms of MDSCs recruitment and their suppression on T cells, as well as current therapeutic strategies targeting MDSCs.