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.
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.
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.
Wealth of Targets, Slow Progress
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).