MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia

Abstract

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, in comparison with 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-4, 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 in comparison with 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.

VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML

“…28 A more recent study demonstrated a higher frequency of MDSCs in the peripheral blood of AML patients and the expansion of MDSCs is driven by leukemia-derived extracellular vesicles. 29 In line with these findings, we observed an enhanced presence of monocytic MDSCs in the peripheral blood of AML patients. The number of MDSCs was significantly reduced in patients achieving complete remission after induction chemotherapy.…”

MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs

“…Interestingly, MUC1 silencing did not lead to change in cell viability as determined by annexin/PI analysis in MOLM-14 and THP-1 cells. 66 However, tumor cell proliferation was shown to be reduced in MOLM-14 CRISPR cells as determined by Ki67 analysis (Supplementary Figure 2D). …”

Current challenges for CAR T‐cell therapy of acute myeloid leukemia

“…Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells capable of potently suppressing the function of immune cells. Numbers of circulating MDSCs have been reported to be elevated in AML patients, thereby inhibiting the endogenous immune response and potentially hampering the function of CAR T cells . Thus, reducing the frequency of MDSCs could also prevent leukemic blasts from evading CAR T‐cell treatment.…”

“…Numbers of circulating MDSCs have been reported to be elevated in AML patients, thereby inhibiting the endogenous immune response and potentially hampering the function of CAR T cells. 9 Thus, reducing the frequency of MDSCs could also prevent leukemic blasts from evading CAR T-cell treatment. Preclinical data suggest that administration of CD33/CD3 bispecific antibody (BiTe) can eliminate CD33-expressing MDSCs.…”