Cancer cells are notorious for their camouflage work, which enables them to escape immune targeting. Now scientists are learning how to strip away the disguise and allow the immune system to do its work, by targeting cells called myeloid-derived suppressor cells (MDSCs) that shield the tumor. This would also enhance the effectiveness of newer cancer immunotherapies like Chimeric-Antigen Receptor T cell (CAR-T).
The study was published online in the journal eBioMedicine on August 25, 2019.
What is the principle of this study?
In one sentence, the study is built around selective depletion of MDSCs. These cells are found at higher levels in both the tumor and the blood of cancer patients and indicate a poorer prognosis. Such tumors are likely to be unresponsive to treatment, are more aggressive and spread earlier.
MDSC depletion is important because these cells impair T cell efficacy against cancer, and also reduce the rate of production and the effectiveness of injected CAR-T cells.
Chimeric Antigen Receptor (CAR) on a T-cell is binding to a molecule on a cancer cell surface. Image Credit: Alpha Tauri 3D Graphics / Shutterstock
To understand this, we must understand that cancer cells create their own micro-environment, containing immune cell populations which either target the cancer cells or promote their growth. One of these cell types is the T cell, which normally attacks tumor cells and kills them. Many recent immunotherapies such as CAR-T exploit this ability.
However, the initial promise has been unfulfilled mostly because of the tumor-shielding effects of MDSCs. These suppress the activity of T cells in many ways. For instance, they can produce immune checkpoint molecules on the cell surface, release a host of molecules that modify the immune response, or use up amino acids so that they are not available for protein production.
MDSCs are also involved in other diseases including Haemophagocytic Lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are associated with the depletion of immune cells and severe sepsis.
In a previous experiment, researchers found that specific antibodies produced against mouse MDSCs could bind to and inactivate mouse MDSCs, restoring T cell activity against cancer cells and reduced tumor growth. This serves as proof of concept for the development of targeted MDSC antibodies.
In humans, MDSCs have been poorly studied, but show significant differences from those in mice. MDSCs of various types are identified by different molecules like CD10 and LOX1according to the subtype. There are no antibodies against these subtypes as of now, because no potential drug targets have been identified.
Scientists have recently used immunotoxins to reduce whichever cell they need to deplete. Immunotoxins are antibody-bound toxins directed against one particular type of cell. This approach is now being explored to get rid of MDSCs.
How was the study done?
The scientists used blood and tumor samples from about 200 adults and children with various solid cancers (that is, cancers of solid organs).
They also isolated MDSC cells belonging to the monocytic and granulocytic line, which have surface CD14 and CD15 antigens respectively, from cancer patients. The next step was unique: they sequenced the RNA in these cells to find targets for drug action. This step showed that there were over 300 differences in the genes expressed by these two types of MDSCs. Among these, for the first time 3 were identified as potential immunotoxin targets: CD74, CD 86 and CD33.
The last, CD33, is a protein in the cell membrane that binds a sugar called sialic acid. Thus it is called a sialic acid binding immunoglobulin like lectin (SIGLEC). The immunotoxin targeting it is called gemtuzumab ozogamicin (GO) and has been found to target leukemia cells.
CD33+ MDSCs rapidly bind and carry antibodies inwards to the interior of the cell. However, antibodies do not kill the MDSCs, whereas immunotoxins selectively destroy these cells.
Tumor and blood samples from the 200 cancer patients showed a higher number of CD33 cells compared to other tissues. These cells suppressed T cell counts in cancer patients, but not in healthy donors. This explains why this antigen is associated with cancer-induced immunosuppression.
When treated with GO, the monocytic MDSCs (M-MDSCs) selectively bind to the toxin which is transported into the cells. As a result these CD33 cells are damaged, showing signs of membrane weakening, loss of proliferative activity, and signs of apoptosis or programmed cell death. As a result, normal T cell proliferation was restored in these cultures.
Until now, infused CAR-T cells have shown a rapid fall in number due to circulating and tumor-associated MDSCs. In laboratory cultures, MDSCs suppressed CAR-T cells directed against 3 tumor cell antigens, but this was reversed following the infusion of GO. CAR-T cells also became better at killing off tumor cells after the GO-induced death of MDSCs. MDSC targeting could thus allow solid tumors to be treated using CAR-T for the first time.
GO treatment depletes MDSCs and thus enhances T cell tumor kill across all T cell pathways, rather than indirectly modifying the immune response. Since other bone marrow cells like granulocytes do not have CD33, they do not bind the GO and are spared, further strengthening the immune response.
This research is important in directly targeting myeloid cells that play a role in tumor immunosuppression for the first time. GO has completed phase III clinical adult trials and is being tested for its role in children with cancer. It could therefore be tested for its role in conjunction with existing therapies in both groups of patients. It may be able to convert immunologically unresponsive tumors into highly responsive ones by killing off MDSCs and thus removing a major source of immunosuppression. The researchers plan to begin a phase III trial (GOTHAM) to explore the utility of GO in relapsed or nonresponsive solid tumors, as well as in the deadly HLH and MAS disease conditions.
Francis Mussaia says, “This is the first time we've been able to effectively target the immune cells that form a barrier around solid tumors. If this approach works in patients it could improve treatments for many different types of cancer, in both adults and children. We envision our approach will have the most impact in CAR-T therapy.”
MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers. Livingstone Fultanga,Silvia Panettia, Margaret Ngb, Paul Collinsa, Suzanne Graefa, Nagy Rizkallaa, Sarah Bootha, Richard Lentona, Boris Noyvertc, Claire Shannon-Lowea, Gary Middletona, Francis Mussaia, & Carmela De Santoa. eBioMedicine. https://doi.org/10.1016/j.ebiom.2019.08.025. https://www.ebiomedicine.com/article/S2352-3964(19)30547-X/fulltext