Myeloid-Derived Suppressor Cells (MDSCs) are myeloid cells that contribute to immune tolerance, disease progression and poor outcomes in diseases. The aetiology underlying the expansion of MDSCs and their function in Acute Myeloid Leukemia (AML) has not been clarified hence the rationale for this study.
In this study, primary AML cells from AML patients and human AML cell lines, MOLM-14 and THP-1, were used to investigate the presence and function of MDSCs and also the mechanisms underlying its expansion.
The key results are:
- Mean level of circulating MDSCs in AML patients (n = 9) and healthy controls; 7.94% vs 0.2%, P< 0.05
- There was a significant expansion of MDSCs in MOLM-14, THP-1 and patient derived AML cells; n = 3, P < 0.05
- Compared to control, co-culture of MOLM-14 and THP-1 expanded MDSCs with T- cells significantly inhibited T- cell proliferation, reduced T cell activation markers and IFN-ϒ intracellular expression by 40% and 46% respectively and significantly increased intracellular expression IL-10 cytokine by 13- fold; n = 3, P < 0.05.
- Extracellular Vesicles (EVs) are released by MOLM-14 and THP-1 cells
- MDSCs trafficked EVs from MOLM-14 cells into the MDSCs population
- MOLM-14 EVs co-cultured with Peripheral Blood and Bone Marrow Cells (PMBCs) showed a significant increase in MDSCs population and a 90% reduction in cells exhibiting antigen presenting cell phenotype.
- 60% mean reduction in MDSCs expansion was observed in MUC1 silenced MOLM-14 and THP-1 cells compared to control; P < 0.05
- Reduced expression in c-myc and MUC1 was observed in MUC1 silenced MOLM-14 and THP-1 cells and also in the EVs derived from these cells
- Overexpression of miR34a, a p53 inhibitor, reduced c-myc expression and significantly decreased MDSCs expansion in MOLM-14 and THP-1 cells
- Compared to control cell lines, MUC1 silenced MOLM-14 and THP-1 cells had increased miR34a expression; n = 3, P < 0.05
In AML, MDSCs reservoir are expanded and they can contribute to tumor-related immune suppression in this disease. Additionally, miR34a acts as the regulatory mechanism by which MUC1 oncoprotein drives the promotion of c-myc expression in secreted tumor-derived EVs and AML cells which in turn drives MDSCs expansion.
In conclusion, MUC1 is a critical mediator of MDSCs expansion. The authors suggested that targeting MDSCs via inhibitors or MUC1 inhibition can be useful in improving responses to immunotherapies in AML patients.
Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in Acute Myeloid Leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, compared to normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b+ Gr1+ MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-14, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact dependent expansion of MDSCs. MDSCs were suppressive of autologous T cell responses as evidenced by reduced T cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived Extracellular Vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken up myeloid progenitor cells resulting in the selective proliferation of MDSCs as compared to functionally competent antigen presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.