Immunotherapies, such as Chimeric-Antigen Receptor T cell (CAR-T), often fail because they act within immunosuppressive microenvironments mainly created by Myeloid-Derived Suppressor Cells (MDSCs) in the tumors and blood of patients. MDSCs suppress T cell activity through several mechanisms including expression of immune checkpoint surface molecules, release of nitric oxide or reactive oxide species, production of immunomodulatory cytokines, or the consumption of amino acids. The findings of this study suggest a new approach could help to boost the effects of innovative cancer treatments, namely CAR-T therapy, which so far hasn't been used successfully to tackle solid tumors. Researchers set out to investigate potential clinically relevant targets for depleting MDSCs to reactivate T cell immunity.
The team used RNA sequencing of Monocytic-MDSCs and Granulocytic-MDSCs from blood samples taken from patients. They generated a RNA-sequencing library from both M-MDSCs and G-MDSCs. It reveals a clear separation of the MDSC at the transcriptomic level, confirming that these populations are indeed distinct. They focused on screening the library for potential clinical targets to deplete MDSCs.
Using flow cytometry and immunohistochemistry they showed that the protein CD33 was expressed on the surface of MDSCs across a wide range of cancers. Then MDSCs were treated with Gemtuzumab ozogamicin and the effect of t cell proliferation and CAR-T therapy cytotoxicity were identified using flow cytometry, confocal and electron microscopy. The researchers were able to fully deplete the MDSCs in the samples and restore the ability of T-cells to attack the tumor cells. The findings of this study could have major clinical implications for the use of Gemtuzumab ozogamicin as an adjunct to chemotherapies or immunotherapies, with those possessing the highest frequencies of MDSCs benefitting the most.
In addition to treating a range of cancers, the findings could also be applicable to treating HLH (hemophagocytic lymphohistiocytosis) and MAS (macrophage activation syndrome) - where the body reacts inappropriately to triggers, such as infections. These disorders are extremely rare and as a result there are few treatments available, particularly to children with HLH. Co-treatment of immunotherapy and Gemtuzumab ozogamicin could offer a superior treatment plan for these patients.
Dr Francis Mussai, lead author of the study says that “our research indicates that giving this antibody drug alongside immunotherapies could dramatically increase the number of patients benefitting from the latest innovations in treatment."
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