Myeloid-Derived Suppressor Cells

Abstract

Myeloid cells developed evolutionarily as a major mechanism to protect the host. They evolved as a critical barrier against infections and are important contributors to tissue remodeling. However, in cancer, myeloid cells are largely converted to serve a new master-tumor cells. This process is epitomized by myeloid-derived suppressor cells (MDSC). These cells are closely related to neutrophils and monocytes. MDSCs are not present in the steady state of healthy individuals and appear in cancer and in pathologic conditions associated with chronic inflammation or stress. These cells have emerged as an important contributor to tumor progression. Ample evidence supports a key role for MDSCs in immune suppression in cancer, as well as their prominent role in tumor angiogenesis, drug resistance, and promotion of tumor metastases. MDSCs have a fascinating biology and are implicated in limiting the effects of cancer immunotherapy. Therefore, targeting these cells may represent an attractive therapeutic opportunity. Cancer Immunol Res; 5(1); 3-8. ©2016 AACR.

Figure. Development and function of MDSC

Tumor derived factors affect different stages of myeloid cell differentiation resulting in generation of pathologically activated M-MDSC and PMN-MDSC. HSC-hematopoietic stem cells; CMP – common myeloid progenitor; GMP-granulocyte-macrophage progenitor; MDP – macrophage/dendritic cell progenitors. PMN-MDSC and M-MDSC migrate to lymphoid organs and to tumor site. The function and fate of these cells is different in different sites. In peripheral lymphoid organs PMN-MDSC retain high level of various ROS and cause antigen-specific T-cell suppression/tolerance. M-MDSC produce large array of different factors that enable these cells suppress not only antigen-specific but also non-specific T cell responses. M-MDSC maintain high activity of STAT3 that prevent their quick differentiation to DCs or macrophages. In tumor site, largely due to the effect of hypoxia STATA3 activity in MDSC is dramatically reduced. This result in rapid differentiation of M-MDSC to tumor associated macrophages (TAM). ROS level in PMN-MDSC is substantially reduced, but up-regulation of arginase 1(ARG1) and other factors responsible for nonspecific T-cell suppression is increased. The same happens with M-MDSC. PMN-MDSC are dying rapidly. Factors released by dying cells can contribute to immune suppressive mechanisms.