Myeloid Cell Subtype Attracts Growing Interest as Immune System Target

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.

A Hallmark of Disease

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.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).

The amino acid L-arginine is very important for the correct functioning of the T-cell receptor (TCR), which activates the T cell in response to an antigen, and for the general activity of the T cell. Arginase and iNOS both metabolize L-arginine; thus, if MDSCs produce high levels of these enzymes, they deplete the levels of L-arginine available to T cells and thereby suppress their activity. iNOS is also involved in the production of nitric oxide, which downregulates the JAK/STAT signaling axis that is crucial to T-cell survival.

Meanwhile, ROS disrupts the physical interaction between the TCR and the major histocompatibility complexes on antigen-presenting cells. In addition to suppressing the activity of T cells, MDSCs are thought to drive the recruitment of regulatory T cells, which are naturally immunosuppressive T cells, to the tumor microenvironment by the production of cytokines such as transforming growth factor beta (TGFβ) and interleukin 10 (IL-10).

MDSCs also impact the innate immune response, primarily by inhibiting the cytotoxic activity of NK cells, but also through crosstalk with, and an ability to differentiate into, a protumoral form of macrophage, the tumor-associated macrophage (TAM). Unlike normal macrophages, TAMs are inefficient in producing proinflammatory factors like IL-12 and tumor necrosis factor alpha (TNFα); instead, produce immunosuppressive substances such as TGFβ and IL-10.

Beyond Immunosuppression

It has become apparent that different types of MDSCs use different mechanisms of immunosuppression. For example, M-MDSCs predominantly employ nitric oxide and cytokines to suppress both antigen-specific and nonspecific T-cell responses, while PMN-MDSCs are thought to be more weakly immunosuppressive, depending mainly on the production of ROS to directly inhibit T cells in an antigen-specific manner. Furthermore, of the vast array of immunosuppressive mechanisms that have been elucidated, there is most likely to be only 1 dominant mechanism in play at any time in a particular cancer type and that may differ according to the site of the cancer or as the disease progresses.More recently, novel roles for MDSCs in the development and progression of cancer have been elucidated that are independent of their immunosuppressive capabilities. They are thought to contribute greatly to other aspects of tumor growth, such as angiogenesis, the epithelial-to-mesenchymal transition (EMT), establishment of a premetastatic niche, and metastatic invasion.

There is a growing body of evidence that MDSCs play a key role in all of the steps that lead to the spread of tumors to a secondary site. PMN-MDSCs within the tumor microenvironment have betableen shown to produce hepatocyte growth factor and TGFβ.

These are 2 key factors involved in EMT, the process by which cancer cells lose epithelial markers and differentiate to cells with more mesenchymal features that are important for invasion and migration, thus improving their chances of disseminating around the body and colonizing distant organ sites. It has been suggested that a subpopulation of more dynamic tumor cells with stem cell-like properties, such as the ability to self-renew and take on characteristics of various cell types, may be responsible for the vast majority of metastases. Evidence also points to a role for MDSCs in inducing “stemness” in cancer cells or expanding the cancer stem cell population.

Wealth of Targets, Slow Progress

Finally, MDSCs themselves may have the ability to migrate to, and invade, metastatic sites. The results of several studies have prompted a hypothesis that MDSCs may reach the metastatic site in advance of the tumor cells, where they use a variety of different mechanisms to create an ideal environment, dubbed the premetastatic niche, for the seeding of a secondary tumor.MDSCs have begun to receive significant attention as potential targets for anticancer therapy. In large part, this has not yet advanced beyond the preclinical stage and, when clinical trials have been attempted, it has been with drugs that are already clinically developed as anticancer therapies but which may also have MDSC-targeting properties. The development of drugs that specifically target MDSCs is, as yet, in its infancy.

Researchers have identified several main entry points for anticancer therapy when it comes to MDSCs (Table).

activity. An inhibitor of S100A9, tasquinimod, is one of a select few drugs that were specifically designed to target MDSCs that have reached clinical trials.

Table. Strategies Targeting MDSCs in Selected Clinical Trials

ATRA indicates all-trans retinoic acid; HCC, hepatocellular carcinoma; IL, interleukin; MDSC, myeloid-derived suppressor cells; RCC, renal cell carcinoma; STS, soft tissue sarcoma.

^aStudy is ongoing but not recruiting participants.

Tasquinimod is being jointly developed by Active Biotech and Ipsen and, after promising phase II trials, was advanced into phase III testing in patients with castration-resistant prostate cancer. Disappointing results from the 10TASQ10 study, presented in 2015, showed that tasquinimod did not extend overall survival and development was discontinued in this patient population. A phase II trial in patients with hepatocellular carcinoma, ovarian cancer, renal cell carcinoma, and gastric cancer is ongoing, but not actively recruiting participants (NCT01743469).

Multiple tyrosine kinase receptors, including the vascular endothelial growth factor receptor (VEGFR) and its ligand VEGF, as well as c-KIT, are believed to be involved in MDSC formation. VEGF is also among the factors produced by the tumor microenvironment that contribute to the recruitment of MDSCs; it is subsequently produced by the MDSCs themselves and may play a role in some of the nonimmunosuppressive activity of MDSCs. Thus, VEGF-targeting therapies could fulfill multiple roles in inhibiting MDSCs. These and several multitargeted tyrosine kinase inhibitors have been studied in the context of MDSC models and displayed some activity.

MDSC Recruitment

MDSC Function

Bisphosphonates, which inhibit bone-resorbing osteoclasts and have been used to slow down or prevent the bone damage that can occur as the result of bone metastases, also inhibit enzymes that modulate the activity of matrix metalloproteinase 9 (MMP-9), MMP-9 plays a role in the mobilization of newly formed MDSCs from the bone marrow into the circulation. In a preclinical study, the bisphosphonate zoledronic acid, when used in combination with a therapeutic cancer vaccine, reduced the level of intratumoral MDSCs and attenuated tumor growth.To block the recruitment of MDSCs to the tumor site, investigators have focused on targeting tumor-derived factors that serve to attract MDSCs. There are a wealth of therapeutic targets to choose from among the many proinflammatory chemokines, cytokines, and other cell signaling molecules that are thought to be involved. These include CCL2, CXCR2 and CXCR4, TNFα, granulocyte-macrophage colony-stimulating factor (GM-CSF), colony-stimulating factor receptor 1 (CSFR1), IL-6, VEGF, and many others. Many of these activate the JAK/STAT signaling pathway, again implicating this axis in the biology of MDSCs.Another promising approach is to block the function of MDSCs in patients with cancer, the focus thus far having been on its immunosuppressive effects. Attempts to stymie its effects on arginine depletion have included testing a variety of arginase, iNOS, and ROS inhibitors.

Most notably, these include the phosphodiesterase- 5 (PDE-5) inhibitors sildenafil and tadalafil that are better known as treatments for erectile dysfunction. Their precise mechanism of action is unclear, but they reduce the expression of both arginase and iNOS, and thus help to mitigate the ability of MDSCs to suppress T-cell activity.

Several clinical trials of both drugs in patients with canbcer are ongoing, including a phase II trial of sildenafil in combination with the histone deacetylase inhibitor valproic acid in patients with recurrent high-grade glioma (NCT01817751) and a phase I/II trial of tadalafil in combination with a mucin-1 vaccine in patients with head and neck cancer (NCT02544880).

MDSC Maturation

MDSC Elimination

Omaveloxolone (RTA 408) is another MDSCspecific drug in clinical development. It inhibits ROS and reactive nitrogen species production and, thus, some of the immunosuppressive functions of MDSCs. The phase I/II REVEAL trial of this drug in combination with the immune checkpoint inhibitors ipilimumab or nivolumab in patients with unresectable or metastatic melanoma is ongoing (NCT02259231).Researchers are also seeking out drugs that could drive the maturation of MDSCs, in essence looking for ways to restart the stalled differentiation of immature myeloid cells and get them back on the right track to forming mature myeloid cells that lack the immunosuppressive abilities of MDSCs. Vitamin D3 and all-trans retinoic acid (ATRA) have both been implicated in this process. A phase II trial of ATRA in combination with ipilimumab is currently ongoing (NCT02403778).The final therapeutic strategy under evaluation is to treat MDSCs like any other cancer cell and attempt to induce cell death. Several chemotherapies have been shown to reduce the numbers of circulating MDSCs, including gemcitabine and 5-fluorouracil.

However, they are unable to reduce MDSC counts to levels of healthy individuals, and tumor recurrence after treatment with these drugs correlates with the re-expansion of the MDSC population. Currently, the focus is on combining chemotherapies with other MDSC-targeting drugs to boost their efficacy, as well as on the development of other drugs that may induce MDSC death.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in New Haven, Connecticut.

Key Research

• Condamine T, Ramachandran I, Youn JI, Gabrilovich DI. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med. 2015;66:97-110.
• Di Mitri D, Toso A, Alimonti A. Molecular pathways: targeting tumor-infiltrating myeloid-derived suppressor cells for cancer therapy. Clin Cancer Res. 2015;21(14):3108-3112.
• Diaz-Montero CM, Finke J, Montero AJ. Myeloid-derived suppressor cells in cancer: therapeutic, predictive, and prognostic implications. Semin Oncol. 2014;41(2):174-184.
• Draghiciu O, Lubbers J, Nijman HW, Daemen T. Myeloid-derived suppressor cells—an overview of combat strategies to increase immunotherapy efficacy. Oncoimmunology. 2015;4(1):e954829.
• Pyzer AR, Cole L, Rosenblatt J, Avigan DE. Myeloid-derived suppressor cells as effectors of immune suppression in cancer. Int J Cancer. 2016;139(9):1915-1926.
• Sternberg C, Armstrong A, Pili R, et al. Randomized, double-blind, placebo-controlled phase III study of tasquinimod in men with castration- resistant prostate cancer. J Clin Oncol. 2016;34(22):2636-2643.
• Wesolowski R, Markowitz J, Carson III WE. Myeloid derived suppressor cells—a new therapeutic target in the treatment of cancer. J Immunother Cancer. 2013;1:10-21. doi:10.1186/2051-1426-1-10.