Myeloid-Derived Suppressor Cells (MDSC) – Function & Role

What Are Myeloid-Derived Suppressor Cells?

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells belonging to the innate immune system. They originate in the bone marrow as part of the myeloid lineage, which also includes granulocytes, monocytes, and dendritic cells. Under normal physiological conditions, these precursor cells mature into fully functional immune cells. However, in pathological states – particularly cancer, chronic infections, and autoimmune diseases – their differentiation is blocked, causing them to accumulate in the blood, spleen, and tumor tissues.

Origin and Classification

MDSCs arise when the body is exposed to persistent inflammatory signals. Specific cytokines and growth factors – including IL-6, IL-10, VEGF, and GM-CSF – interfere with the normal maturation of myeloid progenitor cells, leading to the expansion of immunosuppressive immature cells.

Two main subpopulations are distinguished:

• Polymorphonuclear MDSCs (PMN-MDSC): Morphologically similar to neutrophils; they represent the most abundant subtype in most pathological conditions.
• Monocytic MDSCs (M-MDSC): Morphologically resemble monocytes and exhibit particularly potent immunosuppressive activity.

Mechanism of Action

MDSCs suppress immune responses through several molecular mechanisms:

• Arginase-1 and iNOS: These enzymes deplete L-arginine, an amino acid essential for T-cell activation and proliferation, thereby significantly impairing T-cell function.
• Reactive oxygen species (ROS): MDSCs generate high levels of ROS that directly damage T cells and inhibit their activity.
• Immunosuppressive cytokines: By secreting IL-10 and TGF-β, MDSCs suppress the function of other immune cells.
• Promotion of regulatory T cells: MDSCs support the expansion and activity of regulatory T cells (Tregs), which further dampen immune responses.
• Inhibition of NK cells: Natural killer (NK) cells, which are critical for tumor surveillance, are also functionally impaired by MDSC-mediated suppression.

Clinical Significance

Cancer

In oncology, MDSCs play a central role in enabling tumors to evade immune destruction. Tumor cells actively exploit MDSCs to create an immunosuppressive microenvironment. Elevated MDSC levels in the blood or tumor tissue have been associated with a worse prognosis across many cancer types, including breast, lung, colorectal, and pancreatic cancer. In addition, MDSCs can promote metastasis by establishing immunosuppressive niches at sites of distant spread.

Chronic Infections and Sepsis

In chronic infectious diseases such as HIV, tuberculosis, and hepatitis, as well as in sepsis, MDSCs accumulate and contribute to immune paralysis. This impairs the body's ability to eliminate pathogens and can worsen clinical outcomes.

Autoimmune Diseases and Transplantation

In certain contexts – such as organ transplantation or autoimmune conditions – the immunosuppressive activity of MDSCs may actually be beneficial. Research is ongoing into whether MDSCs can be deliberately expanded to prevent transplant rejection or dampen autoimmune responses.

Diagnosis and Detection Methods

MDSCs are primarily identified and characterized using flow cytometry, which analyzes specific surface markers. PMN-MDSCs typically express CD11b+, CD14-, CD15+, and CD33+, while M-MDSCs are characterized by CD11b+, CD14+, HLA-DR-/low, and CD15-. Because MDSCs lack entirely uniform markers, internationally standardized definitions developed by groups such as the MDSC Nomenclature Workshop are necessary for consistent research and clinical assessment.

Therapeutic Strategies

Given their central role in tumor immune evasion, MDSCs have become an important target in modern cancer immunotherapy. Current therapeutic approaches include:

• Reducing MDSC accumulation: Phosphodiesterase-5 inhibitors (e.g., sildenafil) and certain chemotherapeutic agents (e.g., gemcitabine) have been shown to reduce MDSC numbers.
• Blocking immunosuppressive mechanisms: Arginase inhibitors and iNOS inhibitors are under investigation in clinical trials.
• Combination with checkpoint inhibitors: Combining MDSC-targeting agents with immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) is being intensively studied to enhance immunotherapy efficacy.
• Promoting differentiation: Vitamin D3, all-trans retinoic acid (ATRA), and other agents can induce MDSCs to differentiate into mature, functional immune cells.

References

1. Veglia, F., Sanseviero, E. & Gabrilovich, D. I. (2021). Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nature Reviews Immunology, 21(8), 485–498. https://doi.org/10.1038/s41577-021-00532-3
2. Bronte, V. et al. (2016). Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nature Communications, 7, 12150. https://doi.org/10.1038/ncomms12150
3. Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. (2016). The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends in Immunology, 37(3), 208–220. https://doi.org/10.1016/j.it.2016.01.004