Interaction Between MDSC and NK Cells in Solid and Hematological Malignancies: Impact on HSCT

Abstract

Myeloid derived suppressor cells (MDSC) are heterogeneous populations that through the release of soluble factors and/or by cell-to-cell interactions suppress both innate and adaptive immune effector cells. In pathological conditions, characterized by the presence of inflammation, a partial block in the differentiation potential of myeloid precursors causes an accumulation of these immunosuppressive cell subsets both in peripheral blood and in tissues. On the contrary, NK cells represent a major player of innate immunity able to counteract tumor growth. The anti-tumor activity of NK cells is primarily related to their cytolytic potential and to the secretion of soluble factors or cytokines that may act on tumors either directly or indirectly upon the recruitment of other cell types. NK cells have been shown to play a fundamental role in haploidentical hemopoietic stem cell transplantation (HSCT), for the therapy of high-risk leukemias. A deeper analysis of MDSC functional effects demonstrated that these cells are capable, through several mechanisms, to reduce the potent GvL activity exerted by NK cells. It is conceivable that, in this transplantation setting, the MDSC-removal or -inactivation may represent a promising strategy to restore the anti-leukemia effect mediated by NK cells. Thus, a better knowledge of the cellular interactions occurring in the tumor microenvironment could promote the development of novel therapeutic strategies for the treatment of solid and hematological malignances.

Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma

“…Moreover, inflammatory mediators, such as IL8 and IL1β and IL13, drive their accumulation and contribute to their inhibitory activity. In addition, MDSC can induce macrophage polarization towards a M2 profile, inhibit NK cell-mediated anti-tumor activity and recruit regulatory T-cells [ 25 ]. Of note, the different immunophenotypic characteristics of MDSC and their suppressive mechanisms of MDSCs reflect their heterogeneous nature [ 25 , 26 ].…”

“…In addition, MDSC can induce macrophage polarization towards a M2 profile, inhibit NK cell-mediated anti-tumor activity and recruit regulatory T-cells [ 25 ]. Of note, the different immunophenotypic characteristics of MDSC and their suppressive mechanisms of MDSCs reflect their heterogeneous nature [ 25 , 26 ]. Therefore, different approaches are required for targeting human MDSC.…”

PD-1/PD-L1 in Cancer: Pathophysiological, Diagnostic and Therapeutic Aspects

“…In different tumor types, increased PD-L1 + MDSC has been detected and, in some instances, a correlation between the percentage of PD-L1 + MDSC and disease stages or clinical outcome has been reported [ 148 ]. In addition, Nitric Oxide (NO) produced by MDSCs has a potent inhibitory effect on NK cells by impairing the Fc receptor-mediated killing, the secretion of IFN-γ, TNF-α and Granzyme B, as detected in MDSC-co-cultured NK cells [ 149 , 150 ]. Other important cells, which favor tumor growth and inhibit antitumor immune responses, are the polarized M2 macrophages, which act both directly by secreting different inhibitory factors and cytokines, and indirectly by inducing suppressive cells and favoring fibrotic reactions [ 151 ].…”

NK Cell Anti-Tumor Surveillance in a Myeloid Cell-Shaped Environment

“…MDSCs can affect NK cell phenotype in the tumor microenvironment and hijack their anti-tumoral potential by direct cell-to-cell interaction and/or by release of soluble factors such as PGE 2 , TGF-beta, IL-10, IL-6 and IL-23. The mechanisms underlying MDSC/NK functional interaction have been comprehensively reviewed recently (57,58).…”