Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation

Abstract

Among the various immunological and non-immunological tumor-promoting activities of myeloid-derived suppressor cells (MDSCs), their immunosuppressive capacity remains a key hallmark. Effort in the past decade has provided us with a clearer view of the suppressive nature of MDSCs. More suppressive pathways have been identified, and their recognized targets have been expanded from T cells and natural killer (NK) cells to other immune cells. These novel mechanisms and targets afford MDSCs versatility in suppressing both innate and adaptive immunity. On the other hand, a better understanding of the regulation of their development and function has been unveiled. This intricate regulatory network, consisting of tumor cells, stromal cells, soluble mediators, and hostile physical conditions, reveals bi-directional crosstalk between MDSCs and the tumor microenvironment. In this article, we will review available information on how MDSCs exert their immunosuppressive function and how they are regulated in the tumor milieu. As MDSCs are a well-established obstacle to anti-tumor immunity, new insights in the potential synergistic combination of MDSC-targeted therapy and immunotherapy will be discussed.

A Uracil Auxotroph Toxoplasma gondii Exerting Immunomodulation to Inhibit Breast Cancer Growth and Metastasis

“…Noteworthily, Tregs are FoxP3 + CD4 + T cells that regulate immune tolerance, and suppress DCs maturation and CD8 + T cells recruitment to the TME [60]. MDSCs play an important role in inhibiting the activation of T cells and NK cells and other immune cells [61]. TAMs, usually display an anti-in ammatory M2-like phenotype, are frequently associated with tumor growth and metastasis [62], and suppress CD8 + T cell recruitment to the TME [63].…”

Transforming growth factor‐beta1 and myeloid‐derived suppressor cells: A cancerous partnership

“…MDSCs are a heterogeneous population consisting of myeloid progenitor cells and immature myeloid cells, characterized by the lack of surface markers associated with fully differentiated myeloid cells and their morphological resemblance to granulocytic and monocytic cells. 14,72 Studies from 1960-80s have established that cancer development is commonly associated with pathological expansion and activation of groups of myeloid cells. 14,[73][74][75][76] Myeloid cells exhibit an immature phenotype initially described in mouse models bearing human tumors and later discovered in patients with head and neck squamous cell cancer (HNSC).…”

“…14,72 Studies from 1960-80s have established that cancer development is commonly associated with pathological expansion and activation of groups of myeloid cells. 14,[73][74][75][76] Myeloid cells exhibit an immature phenotype initially described in mouse models bearing human tumors and later discovered in patients with head and neck squamous cell cancer (HNSC). [77][78][79] In 2007, the term myeloid-derived suppressor cells was coined, 80 and they are recognized as a hallmark of cancer progression and as a central mechanism of immune surveillance evasion by cancer cells due to their immunosuppressive potency.…”

“…171 In turn, M-MDSCs from melanoma patients can inhibit T-cell proliferation ex vivo via paracrine TGF-β1 production, as was demonstrated by specific neutralizing anti-TGF-β1 monoclonal antibodies. 14,172 Moreover, MDSCs-derived TGF-β1 increases PD-1 expression in CD8 + T-cells, contributing to PD-1/ PD-L1 therapy resistance within TME. 173…”

CD38 and Regulation of the Immune Response Cells in Cancer

“…CD38 high B reg cells produce IL-10, which inhibits T naïve cell differentiation to Th1 and Th17 cells while supporting the proliferation of T regs [ 32 , 33 ]. The immunosuppressive role of myeloid-derived suppressor cells (MDSCs) is strongly expanded in the cancer microenvironment [ 29 ], which is well documented. CD38 expression is considered as a marker of MDSCs activity and CD38 high MDSCs have more prominent immune suppressive effects.…”