Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Cancer and Immunotherapy.

Saman Maleki Vareki,Mithunah Krishnamoorthy,Lara Gerhardt

doi:10.3390/cells10051170

Saman Maleki Vareki, Mithunah Krishnamoorthy + Show 1 more

Open Access

https://doi.org/10.3390/cells10051170

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Journal: Cells	Publication Date: May 11, 2021
Citations: 39	License type: CC BY 4.0

Affiliation: Lawson Health Research Institute, Western University

Abstract

The primary function of myeloid cells is to protect the host from infections. However, during cancer progression or states of chronic inflammation, these cells develop into myeloid-derived suppressor cells (MDSCs) that play a prominent role in suppressing anti-tumor immunity. Overcoming the suppressive effects of MDSCs is a major hurdle in cancer immunotherapy. Therefore, understanding the mechanisms by which MDSCs promote tumor growth is essential for improving current immunotherapies and developing new ones. This review explores mechanisms by which MDSCs suppress T-cell immunity and how this impacts the efficacy of commonly used immunotherapies.

Highlights

Myeloid cells make up the largest group of nucleated cells of hematopoietic origin [1].Myeloid cells are a critical part of the innate immune system in healthy individuals, functioning to clear infections and remodeling tissues
Many of the immunosuppressive factors produced by myeloid-derived suppressor cells (MDSCs) that contribute to effector T-cell suppression such as transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), IL-10, and IL-6 are shown to induce a stem-like phenotype in various tumor cells [91,92]
Using colon adenocarcinoma (MC38) and mammary (EMT6) mouse models, this study revealed that therapeutic blockade of TGF-β with antibodies promoted CD8+ T-cell inflammation and anti-tumor immunity, sensitizing tumors to PD-L1 therapy [113]

Summary

Introduction

Myeloid cells make up the largest group of nucleated cells of hematopoietic origin [1]. PMN-MDSCs are defined by the surface expression of CD11b+ Ly6G+ Ly6Clow and CD14− CD11b+ CD15+ (CD66b+ ), respectively [16] These cells mainly promote tumor progression by inducing tolerance in antigen-specific T-cells. Many of these factors trigger the activation of Janus kinase (JAK) protein family members and signal transducer and activator of transcription 3 (STAT3), which are signaling molecules involved in cell survival, proliferation, differentiation, and apoptosis [24] Evidence of this is observed in tumor-bearing mice that have increased levels of phosphorylated STAT3 in MDSCs compared to immature myeloid cells from naive mice. The depletion of MCL-1 in mice leads to an absence of PMN-MDSCs [30]

T-Cell Suppression by MDSCs

Role of MDSCs in Resistance to Immunotherapeutics

MDSCs and Microbiome

Immunotherapies and Combination Strategies Targeting MDSCs

Findings

Conclusions