Immune checkpoint inhibitors (ICIs) have dramatically changed the therapeutic approach to cancer, with antibodies against CTLA-4, PD-1, and PD-L1 demonstrating a durable response in selected patients across multiple tumor types.
These antibodies aren’t universally effective, however. Some patients do not respond to ICIs, suggesting that they may not be effectively stimulating the antitumor immune system. What’s stopping them?
One answer may lie in Myeloid Derived Suppressor Cells (MDSCs).
MDSCs in Immuno-Oncology
MDSCs come in many varieties. There are two major categories, though it can be challenging to discriminate between the two.
Monocytic m-MDSC
m-MDSCs are phenotypically and morphologically similar to monocytes. In mouse syngeneic breast cancer models, m-MDSCs appear to facilitate tumor cell dissemination from the primary site by inducing epithelial to mesenchymal transition (EMT) and producing a cancer stem cell (CSC) phenotype.
Clinically, responders to anti-CTLA-4 have fewer circulating m-MDSCs compared to non-responders. For patients that fail anti-CTLA-4 therapy, higher levels of peripheral blood MDSCs before treatment successfully predicted a subsequent lower response rate to anti-PD-1 therapy.
Patients with more m-MDSCs also had higher rates of disease progression and shorter overall survival in melanoma and non small cell lung cancer (NSCLC).
Granulocytic g-MDSC
The other subtype of MDSCs are g-MDSCs. These cells are more phenotypically and morphologically similar to neutrophils. In a preclinical mouse syngeneic breast tumor model, g-MDSCs from the lungs appeared to suppress the EMT/CSC phenotype and promote cell proliferation.
In humans, g-MDSCs are known to play a role in materno-fetal tolerance. Cord and peripheral blood from pregnant women contain elevated levels of g-MDSCs compared to non-pregnant controls, and these g-MDSCs can prevent fetal immunologic rejection. m-MDSCs in the same analysis are unchanged.
It’s intriguing to speculate that they could play a similar role in cancer; circulating and tumor g-MDSCs are elevated in distinct tumor types, such as colorectal cancer.
Immune Suppressive Effects of MDSCs
MDSCs are often found among the diverse cell types that comprise the tumor infiltrating lymphocyte (TIL) population. Patients with CRC, melanoma, and other cancers routinely exhibit elevated MDSC levels, while their numbers are trivial or nonexistent in healthy patients.
MDSCs can exert suppressive effects on multiple immune cell types, including T cells and NK cells. Functionally distinct from neutrophils and monocytes, MDSCs suppress immune cell activity using a number of pathways, including the upregulation of arginase-1 (Arg1). This leads to arginine starvation and the upregulation of reactive oxygen species (ROS), such as the inducible nitric oxide synthase (iNOS).
MDSCs in Peripheral Blood of Cancer Patients
Intriguingly, the number of MDSCs in the peripheral blood has also been reported to correlate with clinical outcome, for melanoma patients undergoing anti-CTLA-4 therapy.
A retrospective study found that the MDSC population was unaffected by either surgical resection or anti-CTLA-4 treatment, despite the correlation with response to anti-CTLA-4. Taken together, these data may implicate MDSCs in a potential role in immune suppression.
MDSC-Targeted Immuno-Oncology Therapeutics
There are several current therapeutic strategies targeting MDSCs.
MDSC Proliferation and Migration
One approach is the targeting of MDSC proliferation and migration to both reduce MDSC numbers and prevent their presence in the tumor microenvironment.
Small and large molecule therapeutic agents targeting the colony stimulating factor -1 (CSF1)/CSF-1 receptor, the stem cell factor (SCF)/c-Kit receptor, or the IL-6/IL-6R are potential points of therapeutic intervention. All of these signaling axes play a role in normal myeloid lineage development, and inhibition of these signaling pathways has a marked effect on the MDSC population in preclinical models.
Controlling the MDSC Population
Other approaches take advantage of broad spectrum effects of therapeutic agents that impact the MDSC population. This includes molecules like all trans retinoic acid (ATRA) or vitamin D3, which can differentiate MDSCs into more mature cells such as dendritic cells (DCs) and stimulatory monocytes.
Some cytotoxic agents can also eliminate MDSCs, such as sunitinib, gemcitabine, and docetaxel, and are potentially effective at lower doses than those used for targeting tumor cytotoxicity.
Inhibiting MDSC Functionality
Finally, approaches attempting to inhibit the functionality of MDSCs are also being investigated. These agents include phosphodiesterase 5 (PDE-5) inhibitors or COX-2 inhibitors, which can reduce arginase or ROS release to pre-empt the immuno-suppressive effects of MDSCs.
Many of these approaches are already under clinical investigation, and only time will tell which has the most clinical significance for improving the efficacy of immune checkpoint inhibitor therapies.
Further Reading
