scholarly journals Knockout Tumor Microenvironment HO-1 Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2782-2782
Author(s):  
Zhen Zhou ◽  
Qin Fang ◽  
Dan Ma ◽  
Danna Wei ◽  
Xiuying Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Microenvironment ◽  
Mouse Models ◽  
Myeloid Leukemia ◽  
Antitumor Effect ◽  
Gene Knockout ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Effect Of Pd ◽  
Acute Myeloid

Abstract Background/Aims: Myeloid-derived suppressor cells (MDSCs) has been shown to be involved in tumor immune escape mechanisms and B cell-specific immunity in Acute myeloid leukemia (AML) patients. In our previous study shown that HO-1 protein have immunomodulatory activity including targeting of immune suppressor cells in the tumor microenvironment. Thus, we decided to assess whether HO-1 could enhance anti-PD-1 treatment and investigate those alterations in the immunosuppressive tumor microenvironment that contribute to the combined antitumor activity. Method: We utilized C57/BL6 (HO-1 knockout) mouse were radiation with 6.5GY once in a row to repress residual immunity. Malignant tumor HL-60 cells respectively (1×107 cells) per animal were injected subcutaneously into the right abdomen. The xenograft mouse models of AML were euthanised on the 14th day after treatment with a PD-1 inhibitor once a day (20 mg/kg). The tumor volumes were measured and calculated by ruler. Survival curve of individual groups was evaluated from the first day of treatment until death using Kaplan-Meier curves. Results: HO-1 gene knockout enhanced the antitumor effect of PD-1 inhibition in xenograft mouse models of AML by reducing tumor growth and increasing survival. HO-1 gene knockout inhibited the immunosuppressive function of both polymorphonuclear (PMN)- and monocytic-myeloid derived suppressor cell (M-MDSC) populations. Analysis of MDSC response to HO-1 gene knockout revealed significantly reduced arginase-1, iNOS, and COX-2 levels, suggesting potential mechanisms for the altered function. We also observed significant alterations in cytokine/chemokine release in vivo with a shift toward a tumor-suppressive microenvironment. Conclusions: Our results demonstrate that HO-1 gene knockout enhances the antitumor effect of PD-1 targeting through functional inhibition of MDSCs and a transition away from an immune-suppressive tumor microenvironment. [Key words] HO-1 gene knockout; PD-1 inhibitor; tumor microenvironment; MDSCs; AML Disclosures No relevant conflicts of interest to declare.

scholarly journals Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells

2020 ◽  
Vol 21 (14) ◽  
pp. 5135
Author(s):  
Edit Kotogány ◽  
József Á. Balog ◽  
Lajos I. Nagy ◽  
Róbert Alföldi ◽  
Valeria Bertagnolo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
Response To Treatment ◽  
Drug Candidate ◽  
Dependent Manner ◽  
Myeloid Derived Suppressor Cells ◽  
Granulocytic Differentiation ◽  
Acute Myeloid

Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response to treatment followed by the increase of the percentage of the Bcl-xlbright and pAktbright cells. Following the induction of Vav1 and the AP-1 complex, a driver of cellular differentiation, FOS, JUN, JUNB, and JUND were elevated on a concentration and time-dependent manner. As a proof of granulocytic differentiation, the cells remained non-adherent, the expression of CD33 decreased; the granularity, CD11b expression, and MPO activity of HL-60 cells increased upon treatment. Finally, viability of HL-60 cells was hampered shown by the depolarization of mitochondria, activation of caspase-3, cleavage of Z-DEVD-aLUC, appearance of the sub-G1 population, and the leakage of the lactate-dehydrogenase into the supernatant. We confirmed the differentiating effect of our drug candidate on human patient-derived AML cells shown by the increase of CD11b and decrease of CD33+, CD7+, CD206+, and CD38bright cells followed apoptosis (IC50: 80 nM) after treatment ex vivo. Our compound reduced both CD11b+/Ly6C+ and CD11b+/Ly6G+ splenic MDSCs from the murine 4T1 breast cancer model ex vivo.

scholarly journals Immunosuppressive role of CD11b + CD33 + HLA‐DR − myeloid‐derived suppressor cells‐like blast subpopulation in acute myeloid leukemia

2020 ◽  
Vol 9 (19) ◽  
pp. 7007-7017
Author(s):  
Shin Young Hyun ◽  
Eun Jung Na ◽  
Ji Eun Jang ◽  
Haerim Chung ◽  
Soo Jeong Kim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Hla Dr ◽  
Acute Myeloid

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

Blood ◽  
2017 ◽  
Vol 129 (13) ◽  
pp. 1791-1801 ◽  
Author(s):  
Athalia Rachel Pyzer ◽  
Dina Stroopinsky ◽  
Hasan Rajabi ◽  
Abigail Washington ◽  
Ashujit Tagde ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Extracellular Vesicles ◽  
Immune Suppression ◽  
Myeloid Leukemia ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Key Points ◽  
Acute Myeloid

Key Points MDSCs are expanded in AML and contribute to tumor-related immune suppression. MUC1 mediates MDSC expansion via the promotion of c-myc expression in secreted extracellular vesicles.

scholarly journals Myeloid-derived suppressor cells level and MUC1 expression in de novo acute myeloid leukemia

2020 ◽  
Vol 51 (4) ◽  
pp. 245-252
Author(s):  
Sarah M. Nawar ◽  
Hala K. Sultan ◽  
Ahmed M. Bedewy ◽  
Amel A. ElNaggar ◽  
Irene L. Mikhael
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Normal Controls ◽  
Acute Myeloid

AbstractBackgroundAcute myeloid leukemia (AML) is the most common acute leukemia occurring in adults. It is an aggressive myeloid neoplasm with maturation arrest of myelopoiesis, leading to an accumulation of myeloblasts in the bone marrow and peripheral blood.ObjectiveTo evaluate alterations in myeloid-derived suppressor cells level and MUC1 gene expression in patients with de novo acute myeloid leukemia concerning disease characteristics and response to induction chemotherapy.Patients and methodsThe study was performed on 50 AML patients and 50 healthy controls. Detection of myeloid-derived suppressor cells (MDSCs) in peripheral blood was performed by mononuclear separation and flow cytometry. MUC1 gene expression was performed by RNA extraction, reverse transcription, and real-time PCR at Hematology Department Medical Research Institute, Alexandria University.ResultsWe have demonstrated that AML patients had both increased presence of MDSCs in peripheral blood as well as MUC1 overexpression in comparison to normal controls. MDSCs showed a significant correlation regarding response to induction chemotherapy on day 28. While MDSCs and not MUC1 are associated with inferior response to induction chemotherapy on day 28.ConclusionThe current data suggested that AML patients exhibit an increased presence of MDSCs as well as MUC1 gene overexpression in comparison with normal controls. While MDSCs showed a significant correlation regarding response to induction chemotherapy on day 28, MDSCs and not MUC1 are associated with inferior response to induction chemotherapy on the same day.

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