Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

Abstract

, respectively).Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets.

Arginase inhibition suppresses lung metastasis in the 4T1 breast cancer model independently of the immunomodulatory and anti-metastatic effects of VEGFR-2 blockade

“…34,[54][55][56] It is, therefore, reasonable to expect that inhibition of the VEGF/VEGFR-2 axis would reverse tumor-mediated immunosuppression or enhance the effects of immunostimulatory antitumor therapies. 31,34,36 In contrast with these observations, however, experimental data show that anti-angiogenic therapy also mobilizes MDSC, which in turn can limit the therapeutic benefit of anti-angiogenic therapy, 26,29,31 and in certain tumor models may even exacerbate metastatic progression. 47,48 The potential mechanisms accounting for those counteracting effects include the secretion of alternative angiogenic factors such as Bv8 and bFGF, 13,29 the production of immune-suppressive molecules, such as iNOS, Arg I, IDO1-2 and PD-L1/2, the expansion of Tregs, the alteration of the IL10/IL12 balance in tumor associated macrophages (TAM) and the secretion of tumor-stimulating factors, such as IL-6, TGFb, PDGF and GM-CSF.…”

“…26 Mobilized MDSC can promote angiogenesis during natural tumor progression, in part through the release of VEGF and MMP-9.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…54-61 Assessment of myeloid cell phenotypic surface markers may have utility in the fields of novel immunotherapy target identification, 6 as well as biomarker discovery to reflect therapeutic efficacy, tumor burden, or treatment failure. Recent literature characterizing cells of the myeloid lineage in cancer patients and animal models highlights their phenotypic and functional variability, 6 including those characterized as myeloid derived suppressor cells 33 and differentiated macrophages. 62,63 To our surprise, we didn’t find significant differences in the expression of the canonical MDSC marker CD33 either in circulation or in the tumor microenvironment.…”

Immune targets and neoantigens for cancer immunotherapy and precision medicine

“…Besides T-cell-intrinsic regulation, T cell activation is also controlled by external factors (extrinsic regulation), such as CD4 + regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), which inhibit the development and function of effector T cells [27,30,54]. These immunosuppressive cells are usually present in high abundance in the tumor microenvironment and inhibit antitumor immunity.…”

“…These include checkpoints or roadblocks (cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1) and its ligand PD-L1) for T cell activation and function [24][25][26], regulatory T cells, other immunosuppressive cells and inhibitory cytokines [27][28][29][30][31][32][33]. To enhance antitumor immunity, it is necessary to remove these roadblocks so that T cells can be fully activated and functional for the eradication of cancer cells.…”