Apolipoprotein A-I mimetic peptide 4F suppresses tumor-associated macrophages and pancreatic cancer progression

Abstract

Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and the inflammatory microenvironment were investigated in vivo. The cytotoxicity of L-4F toward H7 cells was assessed in vitro. Furthermore, we investigated the effects of L-4F on macrophage polarization by analyzing the polarization and genes of mouse bone marrow-derived macrophages in vitro. The results show that L-4F substantially reduced the tumorigenicity of H7 cells. L-4F inhibited inflammation by reducing the accumulation of inflammatory cells, such as IL-17A-, IL-4-, GM-CSF-, IL-1β-, and IL-6-producing cells and Th1 and Th17. Notably, L-4F also decreased the percentage of macrophages in tumor tissues, especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in vitro. Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, indicating that L-4F prevents M2 type macrophage polarization. However, L-4F could not directly attenuate H7 cell invasion or proliferation and did not induce apoptosis. In addition, L-4F potently down-regulated STAT3, JNK and ERK signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 cells. These results suggest that L-4F exhibits an effective therapeutic effect on pancreatic cancer progression by inhibiting tumor-associated macrophages and inflammation.

A Preliminary Study on Blood Lipid Profile in Patients with COVID-19

“…ApoA1, a major protein component of the HDL complex, is involved in "reverse cholesterol transport" by transporting excess cholesterol from peripheral cells back to the liver for excretion. Besides, ApoA1 has an anti-in ammatory characteristic [12], suggest its role in the in ammatory diseases. Previous studies have revealed that serum ApoA1 was associated with the outcome of patients with sepsis and acute respiratory distress syndrome induced by pneumonia, as well as critically ill patients [13][14][15][16].…”

“…ApoA1 and its mimetic peptide D-amino acids (D-4F) exhibit therapeutic potential in treating cancer, in uenza, sepsis and a variety of lung diseases, such as acute respiratory distress syndrome (ARDS), mainly due to its anti-in ammatory, anti-oxidant and anti-apoptotic properties [12,[20][21][22][23]. In addition, it is noteworthy that ApoA1 inhibits IL-6 release and reduces macrophage activation [21].…”

Association Between Pretreatment Serum Apolipoprotein A1 and Prognosis of Solid Tumors in Chinese Population: A Systematic Review and Meta-Analysis

“…First, apoA1 has been proved to negatively alter tumor-permissive features of tumor microenvironment through multiple pathways. These pathways include but are not limited to the following: suppressing the increase in myeloid-derived suppressor cells to decrease tumor volume [51]; reducing the matrix metalloproteinase-9 protein level and activity to inhibit tumor metastasis [52]; increasing the recruitments of tumor cell killing macrophages and CD8 T cells [53]; reducing the level of surviving, a anti-apoptotic protein, responsible for tumor regression [54]. Second, apoA1 and apoA1 mimetic peptides can bind pro-inflammatory or pro-angiogenic phospholipids, such as lysophosphatidic acid.…”

Apolipoproteins and cancer

“…APOA1 mimetic peptides are 18‐amino acid sequences that recapitulate the secondary structure and partial function of APOA1 . APOA1 mimetic peptides were found to inhibit the development of ovarian cancer, breast cancer, colon cancer, and pancreatic cancer both in vitro and in vivo. APOA1 itself could also exert a suppressive effect on ovarian cancer .…”