IL-2 Modulates TAMs Derived Exosomal MiRNAs to Ameliorate Hepatocellular Carcinoma Development and Progression

Abstract

Background. Interleukin-2 (IL-2) is proved to play an irreplaceable role in antitumor regulation in numerous experimental and clinical trials. Tumor-associated macrophages (TAMs) are able to release exosomes to promote the development and progression of hepatocellular carcinoma (HCC) as essential component of microenvironment. In this study, our intention is to explore the effects of the exosomes from TAMs with IL-2 treatment on HCC development. TAMs were collected and cultured from HCC tissues. The exosomes from the TAMs treated with IL-2 (ExoIL2-TAM) or not (ExoTAM) were identified and used to treat HCC cells in vivo and in vitro. The proliferation, apoptosis, and metastasis of HCC cells were measured. The changes of miRNAs in exosomes were explored to clarify the possible mechanisms. Both decrease of cell proliferation and metastasis and increase of apoptosis were observed with ExoIL2-TAM treatment compared with ExoTAMin vivo and in vitro. miR-375 was obviously augmented in ExoIL2-TAM and HCC cells treated with ExoIL2-TAM. Taken together, IL-2 may modulate exosomal miRNAs from TAMs to ameliorate hepatocellular carcinoma development. This study provides a new perspective to explain the mechanism by which IL-2 inhibits hepatocellular carcinoma and implies the potential clinical value of exosomal miRNAs released by TAMs.

Function and biomedical implications of exosomal microRNAs delivered by parenchymal and nonparenchymal cells in hepatocellular carcinoma

“…Modulating TAM exosomal miRNAs provides a new way to suppress HCC. A tumor suppressor miRNA, miR-375, which is enriched in exosomes from IL-2 modulated TAMs, can ameliorate HCC development[ 116 ]. Moreover, propofol can stimulate TAMs to secrete exosomes overexpressing miR-142-3p.…”

Unveiling the Yin-Yang Balance of M1 and M2 Macrophages in Hepatocellular Carcinoma: Role of Exosomes in Tumor Microenvironment and Immune Modulation

“…Therefore, the suppression of TXNIP expression by M2 exosomal miR-27a-3p may disrupt these normal cellular processes, leading to the promotion of cancer stemness, proliferation, drug resistance, migration, invasion, and tumorigenicity in HCC cells [ 131 ]. Chen et al investigated the role of macrophage-derived exosomes in HCC, focusing on the modulation of exosomal miRNAs by IL-2 [ 132 ]. TAMs were isolated from HCC tissues, and their exosomes were treated with IL-2 (ExoIL2-TAM) or left untreated (ExoTAM).…”

“…Furthermore, a specific miRNA, miR-375, was found to be significantly upregulated in ExoIL2-TAM and HCC cells treated with ExoIL2-TAM. This study provides insights into the mechanisms by which IL-2 inhibits HCC and highlights the potential clinical importance of exosomal miRNAs released by TAMs [ 132 ]. Regarding HCC stemness, Wang et al conducted a study to explore the potential of exosomes derived from TAMs in modulating stem cell properties in HCC [ 133 ].…”

Mechanisms of tumor-associated macrophages affecting the progression of hepatocellular carcinoma

“…The malignant level of a tumor is related to the characteristics of cancerous cells and different components in the tumor microenvironment (TME) ( Wang et al, 2014 ; Ge and Ding, 2020 ). These constituents have a pivotal function in connecting inflammatory mediators and tumors ( Chen et al, 2022 ). The TME is a significant site for the interaction between carcinoma cells and the human immune system.…”

“…The levels of exosomes containing microRNA (miR)-375 derived from TAMs subjected to IL-2 (Exo IL2−TAM ) were higher than those TAMs not subjected to IL-2 (Exo TAM ). These exosomes could decrease HCC cells multiplication and metastasis and facilitate apoptosis both in vivo and in vitro ( Chen et al, 2022 ).…”