Breast cancer is the most diagnosed cancer in women globally. There has been significant
progress in its treatment strategies, but advanced or metastatic breast cancer presents a poor prognosis due to drug resistance and recurrences. Tumour microenvironment (TME) further complicates the search for treatment. TME is a complex and dynamic ecosystem where cancer cells use host cells to help their own survival and spread. One of the most critical and challenging components of this environment is Myeloid-Derived Suppressor Cells (MDSCs).
Understanding the MDSC:
MDSCs are a heterogeneous population of immature myeloid cells that originate in the bone marrow. In normal physiological conditions, these precursor cells differentiate to mature, functional immune defenders like macrophages, dendritic cells, or neutrophils. But in the presence of chronic inflammation and pathological stress caused by cancer, this maturation process is hindered. Instead of becoming defenders, these cells remain immature and are reprogrammed into potent suppressors of the body’s natural anti-tumour immunity. In humans, MDSCs are classified into 2 main subsets: monocytic MDSCs (M-MDSCs), which look like monocytes, and granulocytic or polymorphonuclear MDSCs (PMN-MDSCs) which resemble neutrophils. Even though they protect the tumour, recently, advanced single-cell transcriptomic methods have identified specific markers like CD84 as highly selective for MDSCs in breast cancer.
Mechanisms of immune evasion:
MDSCs impact the immune system mainly by targeting T-cells and natural killer (NK) cells
to promote immune escape. This evasion occurs through several distinct pathways.
Nutrient depletion and starvation: MDSCs can impair T-cell function by decreasing
metabolites and factors like L-arginine, cysteine and tryptophan (Trp) which are important for the immune system. MDSCs produce high levels of Arginase-1 (Arg1), converting L-arginine into proline and spermine, which starves the TME of arginine required for T-cell activation and proliferation. T-cells thus enter cell cycle arrest. Similarly, they generate Indoleamine 2,3-dioxygenase (IDO) to deplete tryptophan․
Oxidative and Nitrosative Stress: MDSCs release reactive oxygen species (ROS), nitric oxide (NO), and peroxynitrite (PNT). These agents induce oxidative stress and trigger T-cell apoptosis or chemically alter T-cell receptors (TCRs) to prevent cancer cell recognition.
Recruiting immunosuppressive cells: MDSCs secrete cytokines such as IL-10 and TGF-β,
which inhibit ՛killer՛ immune cells while recruiting and expanding regulatory T-cells (Tregs). They actively enable cancer progression and facilitate angiogenesis and epithelial
mesenchymal transition (EMT). They help establish pre-metastatic niches in distant organs
like the lungs or bone which prepare them for the arrival of migrating cancer cells.
Clinical significance: a new prospect for prediction:
One of the most exciting developments in recent years is the use of MDSCs as biomarkers to predict patient outcomes. Because MDSC levels in the blood can predict aggressiveness and stage of the tumour. Tracking them provides a good non-invasive way to monitor disease progression. In a study using single-cell RNA sequencing, researchers identified a 5-gene risk score (BCL2A1, GDI2, GRINA, RNASE1, and SERPINA1) associated with MDSCs in breast cancer. Patients with high scores were found to have a highly immunosuppressive TME and significantly poorer overall survival.
Furthermore, elevated levels of MDSCs and Tregs in the peripheral blood are robust
predictors of lymph node metastasis. Combining the assessment of these two cell types may
eventually offer a safe, cost-effective alternative to surgical biopsies for staging. An interesting finding is that host factors like obesity exacerbate this problem. Obesity and diet high in fat increase the accumulation of G-MDSCs in the TME, which then causes immunotherapy resistance by inducing T cell apoptosis.
Emerging therapeutic strategies:
How can we overcome these cells? Current research is exploring four main therapeutic
pathways:
Depletion: Low-dose chemotherapies like gemcitabine, 5-fluorouracil (5-FU), and
doxorubicin, have shown to selectively kill MDSCs due to which immune system is no
longer suppressed. Blocking recruitment: MDSCs can be prevented from reaching the
tumour by interfering with the chemical trails they follow. Inhibitors targeting the
CCL2/CCR2 or CXCR2 pathways have shown promise in reducing MDSC infiltration and
slowing tumour growth in preclinical models. Functional Blockade: Strategies are being
developed to target MDSCs by inhibiting their production of Arg1 or ROS. For example, the
Arg1 inhibitor CB-1158 is currently being tested to see if it can restore T-cell function.
Differentiation: Instead of killing them, MDSCs can be stimulated to differentiate into
harmless, mature cells. Drugs like All-trans retinoic acid (ATRA) and Vitamin D have been
shown to induce this maturation and result in cells which are non-suppressive for immune
system.
The future:
In the future, MDSC checkpoint blockade can provide a new development point. Just like we have checkpoints for T-cells (like PD-1), discovery of specific immune checkpoint molecules on MDSCs like VISTA, LILRB, and CD300ld is evolving. The suppressive network of the TME can be disrupted by targeting these molecules with much more precision than traditional chemotherapy. Recent simulations also suggest that combining tumour vaccination with MDSC depletion could not only stop tumour growth but also induce continued dormancy, turning a terminal disease into a manageable chronic condition.
As the understanding of MDSC evolves, another approach for precision oncology is unveiled. Tumour can no longer be targeted alone, the microenvironment that protects it also has to be taken into consideration. By targeting MDSCs, we don’t just attack the cancer, but support the body’s own immune system to finish the job. There has been a change in seeing these cells as just markers of poor prognosis to understanding them as promising therapeutic targets, which gives hope for breast cancer patients globally.
Upasana Pathak