白细胞介素2受体
FOXP3型
免疫系统
化学
细胞毒性T细胞
白细胞介素2
癌症研究
分子生物学
药理学
生物
体外
免疫学
生物化学
作者
Okki Cho,Joong-Woon Lee,Hansol Kim,Youngjin Jeong,Tae‐Hwe Heo
出处
期刊:Life Sciences
[Elsevier]
日期:2023-05-01
卷期号:320: 121559-121559
被引量:4
标识
DOI:10.1016/j.lfs.2023.121559
摘要
In this study, we investigated the inhibition of IL-2 activity and anticancer efficacy of chelerythrine (CHE), a natural small molecule that targets IL-2 and inhibits CD25 binding, and elucidated the mechanism underlying the action of CHE on immune cells. CHE was discovered by competitive binding ELISA and SPR analysis. The effect of CHE on IL-2 activity was evaluated in CTLL-2, HEK-Blue reporter and immune cells, and in ex vivo generation of regulatory T cells (Treg cells). The antitumor activity of CHE was evaluated in B16F10 tumor-bearing C57BL/6 or BALB/c nude mice. We identified that CHE, which acts as an IL-2 inhibitor, selectively inhibits the interaction between IL-2 and IL-2Rα and directly binds to IL-2. CHE inhibited the proliferation and signaling of CTLL-2 cells and suppressed IL-2 activity in HEK-Blue reporter and immune cells. CHE prevented the conversion of naive CD4+ T cells into CD4+CD25+Foxp3+ Treg cells in response to IL-2. CHE reduced tumor growth in C57BL/6 mice but not in T-cell-deficient mice, upregulated the expression of IFN-γ and cytotoxic molecules, and limited Foxp3 expression. Furthermore, the combination of CHE and a PD-1 inhibitor synergistically increased antitumor activity in melanoma-bearing mice and almost completely regressed the implanted tumors. We found that CHE, which targets IL-2 and inhibits its binding to CD25, exhibits T cell-mediated antitumor activity and that combination therapy with CHE and PD-1 inhibitor induced synergistic antitumor effects, suggesting that CHE may be a promising anticancer agent for melanoma monotherapy and combination therapy.
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