Apolipoprotein A-I Mimetic Peptide L-4F Suppresses Granulocytic-Myeloid-Derived Suppressor Cells in Mouse Pancreatic Cancer

Abstract

L-4F is an apolipoprotein A-I (ApoA-I) mimetic peptide, it was engineered to imitate the antiinflammatory and anti-oxidative activity of ApoA-I. In this paper, H7 cell was used to construct a mouse model of pancreatic cancer in situ, and the mice were treated with L-4F. Then, the development of pancreatic cancer and myeloid-derived suppressor cells (MDSCs) infiltration were investigated in vivo. After L-4F treatment, the differentiation, proliferation and apoptosis of MDSCs were detected in vitro. Moreover, we test its effects on the immunosuppressive function of MDSCs ex vivo. The results show that L-4F significantly reduced the tumorigenicity of H7 cells. L-4F suppressed granulocytic myeloid-derived suppressor cells (PMN-MDSCs) differentiation and inhibited the accumulation of PMN-MDSCs in the mouse spleen and tumor tissue. L-4F weakened the immunosuppressive function of MDSCs, resulting in decreased production of ROS and H 2 O 2 by MDSCs, and increased T cell proliferation, interferon g and tumor necrosis factor b secretion, and CD3 + CD4 + T and CD3 + CD8 + T cell infiltration into the mouse spleen and pancreatic cancer tissue. Furthermore, L-4F significantly down regulated the STAT3 signaling pathway in PMN-MDSCs. These results indicated that L-4F exerts an effective anti-tumor and immunomodulatory effect in pancreatic cancer by inhibiting PMN-MDSCs.

Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

“…Apolipoprotein A-I mimetic peptide L-4F can inhibit the differentiation and activation of MDSCs by downregulating the signal transducer and activator of transcription (STAT)3 signaling pathway of MDSCs. L-4F has the potential to be used as an adjunctive drug for ICI treatment [ 109 ]. In 2016, Huang et al [ 110 ] found that ltp-1, another inhibitor of the STAT3 signaling pathway, can inhibit the growth of pancreatic cancer in vivo and in vitro.…”

Prognostic and Therapeutic Value of Apolipoprotein A and a New Risk Scoring System Based on Apolipoprotein A and Adenosine Deaminase in Chronic Lymphocytic Leukemia

“…vivo studies (24,(30)(31)(32)(33)(34)(35)(36)(37)(38). In the hematologic tumors, there was a relatively low level of HDL/ApoA-I in patients with acute lymphoblastic leukemia at diagnosis.…”

HDL and persistent inflammation immunosuppression and catabolism syndrome

“…It also inhibits inflammatory conversion of HDL by hydroperoxyoctanedecanoic acid (HODE precursor). 4F has also been found to reduce MDSC levels, downregulate surface TLRs and deplete cholesterol in lipid rafts [117 ▪ ,118,119]. However, L-4F was active in mice with functional immune systems, which may potentially limit the target population [120].…”