The Development and Homing of Myeloid-Derived Suppressor Cells: From a Two-Stage Model to a Multistep Narrative.

Nathan Karin

doi:10.3389/fimmu.2020.557586

Abstract

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells. Under normal conditions, they differentiate into macrophages, dendritic cells, and granulocytes. Under pathological conditions, such as chronic inflammation, or cancer, they tend to maintain their immature state as immature myeloid cells that, within the tumor microenvironment, become suppressor cells and assist tumor escape from immune eradication. MDSC are comprised of two major subsets: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). Monocytic myeloid cells give rise to monocytic cells, whereas PMN-MDSC share similarities with neutrophils. Based on their biological activities, a two-stage model that includes the mobilization of the periphery as myeloid cells and their activation within the tumor microenvironment converting them into suppressor cells was previously suggested by D. Gabrilovich. From the migratory viewpoint, we are suggesting a more complex setup. It starts with crosstalk between the tumor site and the hematopoietic stem and progenitor cells (HSPCs) at the bone marrow (BM) and secondary lymphatic organs, resulting in rapid myelopoiesis followed by mobilization to the blood. Although myelopoiesis is coordinated by several cytokines and transcription factors, mobilization is selectively directed by chemokine receptors and may differ between M-MDSC and PMN-MDSC. These myeloid cells may then undergo further expansion at these secondary lymphatic organs and then home to the tumor site. Finally, selective homing of T cell subsets has been associated with retention at the target organs directed by adhesion molecules or chemokine receptors. The possible relevance to myeloid cells is still speculative but is discussed.

Highlights

The tumor microenvironment (TME) is the environment around the tumor that includes sounding blood vessels; immune cells; fibroblasts; soluble mediators, such as cytokines, chemokines, and growth factors; and extracellular matrix (ECM)
Population of cells that consists of myeloid progenitor cells and immature myeloid cells (IMCs). These IMCs differentiate into monocytic cells that later become macrophages, dendritic cells (DC), and mature granulocytes
Gabrilovich et al suggest a two-stage model that is based on the biological function of myeloid cells during cancer and chronic inflammation [11]. It includes the myelopoiesis of these cells in bone marrow (BM), their mobilization to the blood and secondary lymphatic organs as myeloid cells, and later their transition and maintenance as Myeloid-derived suppressor cells (MDSC), which mostly takes place at the tumor site [11] or, respectively, sites of chronic inflammation [36]

Summary

INTRODUCTION

The tumor microenvironment (TME) is the environment around the tumor that includes sounding blood vessels; immune cells; fibroblasts; soluble mediators, such as cytokines, chemokines, and growth factors; and extracellular matrix (ECM). It includes the myelopoiesis of these cells in BM, their mobilization to the blood and secondary lymphatic organs as myeloid cells (stage I), and later their transition and maintenance as MDSC (stage II), which mostly takes place at the tumor site [11] or, respectively, sites of chronic inflammation [36] In both type of diseases, the rapid myelopoiesis of myeloid cells at the BM is likely to be directed by several cytokines and transcription factors, among them interleukin-17A (IL-17A) ROR1C that induces IL-17A, G-CSF, GM-CSF, TNFa and THE RECRUITMENT OF MDSC AT TUMOR SITES AS A MULTISTEP EVENT DIRECTED IN PART BY CHEMOKINE– CHEMOKINE RECEPTOR PATHWAYS. In different cancer diseases, poor or good prognosis was associated with high or low levels of these chemokines (Table 2) [for a recent review, see [73]] How could these observations take place with the predominate role of the CCR5-axis for directing PMN-MDSC recruitment and the CCR2-axis for M-MDSC selective recruitment at tumor sites? How could these observations take place with the predominate role of the CCR5-axis for directing PMN-MDSC recruitment and the CCR2-axis for M-MDSC selective recruitment at tumor sites? We are suggesting, within the threestep model described above, the highly selective step that

Colorectal cancer

A FUTURE VIEW OF THE CLASSICAL TWO-STAGE MODEL IN LIGHT OF MODERN TECHNOLOGIES

CONCLUSIONS