Targeting Myeloid-derived Suppressor Cells to Attenuate Vasculogenic Mimicry and Synergistically Enhance the Anti-tumor Effect of PD-1 Inhibitor

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 ◽

10.1182/blood-2018-99-117808 ◽

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.

Download Full-text