As the role that the tumor microenvironment plays in the development of cancer becomes increasingly well understood, a new player has emerged: myeloid-derived suppressor cells (MDSCs).
During the past decade, MDSCs have been identified as a critical immunosuppressive component of the tumor microenvironment—immune accessory cells that help foster diverse mechanisms of immune tolerance and escape.
Now, researchers studying the biology of these cells have uncovered numerous effects of MDSCs on cancer development and progression beyond their impact on the immune system. As a result, MDSCs represent an increasingly attractive therapeutic target and predictive marker in patients with a variety of different cancer types.
A Hallmark of Disease
The existence of cells derived from the bone marrow with potent immunosuppressive effects was noted almost 40 years ago. In the intervening years, our understanding of the origin, nature, and function of these cells has evolved, culminating in the coining of the term myeloid-derived suppressor cells in 2007.
Myeloid cells are one of the largest lineages of cells derived from the bone marrow that circulate in the blood. In healthy individuals, hematopoietic stem cells in the bone marrow give rise to immature myeloid cells, which then differentiate into mature myeloid cells, including macrophages, dendritic cells, and granulocytes, that play an essential role in innate and adaptive immune responses.
Bona fide MDSCs do not really exist in healthy individuals; although there are precursors of mature myeloid cells that share the same phenotype, they do not have the same functions. Instead, MDSCs accumulate during the pathological response to long-term unresolved chronic infection, inflammation, or cancer.
Essentially, MDSCs are a diverse group of immature myeloid cells that have become stuck at various stages of differentiation, unable to form fully mature myeloid cells. They are characterized by their ability to potently suppress the immune response, predominantly through their effects on the major cellular effectors—the T cells and natural killer (NK) cells (Figure)
Figure. MDSCs in Tumor Microenvironment
Myeloid-derived suppressor cells (MDSCs), which do not exist in healthy individuals, interact with many components of the immune system, including dendritic cells, natural killer (NK) cells, macrophages, and T-regulatory (Treg) cells in the process of promoting cancer.
Adapted from Condamine et al. Annu Rev Med. 2015;66:97-110; and Srivastava et al.
In the animal models in which MDSCs have been extensively studied, they are readily identified by several cell surface markers; in humans, however, they have proved to be a little more difficult to characterize, and identifying distinguishing markers is one of the key challenges for oncology researchers. To further complicate matters, there are several different types of MDSCs.
In general, MDSCs are divided into 2 major subsets. The myeloid progenitors and immature mononuclear cells, known collectively as M-MDSCs, are similar to monocytes. Immature polymorphonuclear cells, known as PMN-MDSCs, have similarities to neutrophils. In recent years, studies have identified other distinct subsets of MDSCs that also have important roles in various pathologic conditions.
MDSCs have been identified in almost all types of cancer, and a number of studies have shown a correlation between the number of MDSCs and patient prognosis. In most solid tumors, the predominant type are PMN-MDSCs, with a few notable exceptions, including melanoma, multiple myeloma, and prostate cancer, in which the M-MDSC subset is more prevalent.
Infiltrating the Tumor Microenvironment In the context of cancer, the tumor and the supportive cells surrounding it release numerous substances that drive the dysfunctional development of immature myeloid cells, leading to an expansion of MDSCs within the bone marrow. The MDSCs then begin to accumulate in the circulation and the lymph nodes. Meanwhile, those tumor-derived factors also recruit MDSCs to the tumor microenvironment. This is thought to be an early event in tumorigenesis and, once there, the MDSCs contribute to one of the key hallmarks of cancer—the suppression of the antitumor immune response.
MDSCs exert a multitude of different immunosuppressive effects, and it is thought that the specific mechanisms they employ vary according to the type of cancer or the stage of disease. Best characterized are their effects on T cells, the central players of the adaptive immune response. MDSCs produce several key substances that impact T cells: the enzymes arginase and inducible nitric oxide synthase (iNOS), as well as reactive oxygen species (ROS).