The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression

Abstract

The immunosuppressive tumor microenvironment represents not only one of the key factors stimulating tumor progression but also a strong obstacle for efficient tumor immunotherapy. Immunosuppression was found to be associated with chronic inflammatory mediators including cytokines, chemokines and growth factors produced by cancer and stroma cells. Long-term intensive production of these factors induces the formation of myeloid-derived suppressor cells (MDSCs) representing one of the most important players mediating immunosuppression. Moreover, MDSCs could not only inhibit anti-tumor immune reactions but also directly stimulate tumor growth and metastasis. Therefore, understanding the mechanisms of their generation, expansion, recruitment and activation is required for the development of novel strategies for tumor immunotherapy.

Keywords: immunosuppression; myeloid-derived suppressor cells; myelopoiesis; therapeutic targeting; tumor microenvironment.

Figure 1

Chronic inflammatory factors stimulate myeloid-derived suppressor cells (MDSC) generation, migration and activation of immunosuppressive functions at the tumor site. Various cytokines and growth factors produced by tumor and stroma cells (such as VEGF, GM-CSF, IL-1β, IL-6, HIF-1α, TGF-β, COX-2, etc.) induce MDSC generation and expansion. Chemokines (like CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL8, etc.) stimulate migration of MDSCs into the tumor microenvironment. At the tumor site, MDSCs undergo activation (via TNF-α, IL-10, IL-1β, IL-6, IFN-γ, COX-2, HIF-1α, etc.) and strongly inhibit anti-tumor reactivity of DC, T and NK cells.

Figure 2

MDSCs support tumor development and metastasis. Soluble factors secreted by MDSCs (such as MMPs, VEGF, TGF-β, etc.) can stimulate tumor neovascularization, invasion, proliferation and metastasis.