Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer.

IF 2.9 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yusuke Hamada, Toshiaki Ohara, Yuehua Chen, Manato Terada, Yuze Wang, Hotaka Kawai, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa
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引用次数: 0

Abstract

Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super-polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation in vitro, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment.

铁螯合剂诱导的假性缺氧激活肺癌肿瘤免疫反应。
缺氧诱导因子(HIF)信号在免疫细胞功能中起着至关重要的作用。假性缺氧的特点是铁介导的HIF-1α在常氧条件下的稳定,这可以由铁螯合剂诱导。本研究探讨铁螯合剂是否通过增强肿瘤免疫反应发挥抗肿瘤作用并阐明其机制。铁螯合剂超多酚10 (SP10)和去铁胺(DFO)用于制造缺铁和假性缺氧条件。铁螯合剂诱导的假性缺氧刺激T细胞、人和小鼠非小细胞肺癌(NSCLC)细胞系(A549、PC-3和LLC)分泌IL-2。当C57BL/6小鼠植入LLC肿瘤时,给予SP10可降低肿瘤生长;然而,在rag1免疫缺陷的C57BL/6小鼠中没有观察到这一点。SP10本身在体外不直接抑制LLC细胞的增殖,提示激活肿瘤免疫反应。SP10通过增加肿瘤浸润淋巴细胞(til)的数量,协同增强PD-1抗体治疗肺癌的疗效。综上所述,铁螯合诱导的假性缺氧通过直接上调HIF-1α,增强T细胞功能,诱导T细胞和癌细胞分泌IL-2,从而激活肿瘤免疫应答,从而增强PD-1抗体在肺癌治疗中的免疫功效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Free Radical Research
Free Radical Research 生物-生化与分子生物学
CiteScore
6.70
自引率
0.00%
发文量
47
审稿时长
3 months
期刊介绍: Free Radical Research publishes high-quality research papers, hypotheses and reviews in free radicals and other reactive species in biological, clinical, environmental and other systems; redox signalling; antioxidants, including diet-derived antioxidants and other relevant aspects of human nutrition; and oxidative damage, mechanisms and measurement.
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