Myeloid Derived Suppressor Cells Interactions With Natural Killer Cells and Pro-angiogenic Activities: Roles in Tumor Progression

Abstract

Myeloid-derived suppressor cells (MDSCs) contribute to the induction of an immune suppressive/anergic, tumor permissive environment. MDSCs act as immunosuppression orchestrators also by interacting with several components of both innate and adaptive immunity. Natural killer (NK) cells are innate lymphoid cells functioning as primary effector of immunity, against tumors and virus-infected cells. Apart from the previously described anergy and hypo-functionality of NK cells in different tumors, NK cells in cancer patients show pro-angiogenic phenotype and functions, similar to decidual NK cells. We termed the pro-angiogenic NK cells in the tumor microenvironment "tumor infiltrating NK" (TINKs), and peripheral blood NK cells in cancer patients "tumor associated NK" (TANKs). The contribution of MDSCs in regulating NK cell functions in tumor-bearing host, still represent a poorly explored topic, and even less is known on NK cell regulation of MDSCs. Here, we review whether the crosstalk between MDSCs and NK cells can impact on tumor onset, angiogenesis and progression, focusing on key cellular and molecular interactions. We also propose that the similarity of the properties of tumor associated/tumor infiltrating NK and MDSC with those of decidual NK and decidual MDSCs during pregnancy could hint to a possible onco-fetal origin of these pro-angiogenic leukocytes.

Keywords: angiogenesis; cytokines; decidua; myeloid derived suppressor cell (MDSC); natural killer cells (NK cells); tumor microenvironment.

Figure 1

MDSC and NK crosstalk within the tumor microenvironment (TME). Immunosuppressive activities of MDSCs on NK cells act by diverse molecular and cellular mediators. MDSC affect NK cell functionality by several major released factors, among which TGFβ. TGFβ is produced by MDSC or by MDSC-like cells, originated from PGE2 exposed monocytes. Another mediator is IDO produced directly from MDSCs or from a CD33⁺CD13⁺CD14⁻CD15⁻ subset, derived from CD33⁺ precursors. Adenosine from CD39^highCD73^high MDSCs is a further major NK suppressive factor. MDSC effectors decrease NKG2D, NCRs, IFNγ, TNFα, perforin, granzyme levels and ADCC in NK cells.

Figure 2

MDSC contribution to tumor angiogenesis. MDSCs can support angiogenesis by different mechanisms. Hypoxia within the TME induce VEGF release directly from MDSCs or indirectly following exposure of MDSCs to TGFβ and adenosine. STAT3 activation in MDSCs also support angiogenesis, via IL1-β, CXCL2, and CCL2 secretion. MDSCs contribute to tumor angiogenesis by ECM remodeling via MMP-2/8/9/13/14 release. Finally, given their cell plasticity, MDSCs can transdifferentiate into endothelial-like cells.

Figure 3

Strategies for targeting MDSC and cross-talk with NK. The presented strategies act simultaneously on MDSC and MDSC-released factors dampening NK cell immunosuppression and induction of angiogenesis. (A) MDSC depletion can be induced using low doses of chemotherapy, tyrosine kinase inhibitors, the anti-DR5 monoclonal antibody DS-8273a. (B) Strategies blocking MDSC recruitments by CCL2 inhibitors and CCR5 antagonists. (C) Differentiation of MDSC into non-immunosuppressive cells induced by all-trans-retinoic acid (ATRA), Vitamin D3, and Vitamin E. (D) Inhibition of MDSC immunosuppression can be induced by STAT3 inhibitors, reduction of immunosuppressive agents such as Arginase and ROS, along with attenuation of the inflammatory state.