Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
Core Facility Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
J Transl Med. 2024 May 30;22(1):519. doi: 10.1186/s12967-024-05331-3.
Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms.
Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects.
Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response.
This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC.
端粒酶通过保护受损的端粒并增强 DNA 损伤修复，能够提高肿瘤细胞的放射抵抗能力。因此，它会降低放疗（RT）和放射免疫治疗的疗效。我们之前的研究表明，高选择性端粒酶抑制剂 BIBR1532 具有增强非小细胞肺癌（NSCLC）放射敏感性的潜力。在这项研究中，我们进一步研究了 BIBR1532 对 RT 诱导的免疫激活的影响，并阐明了其潜在机制。
通过生物信息分析、免疫荧光分析、Western blot 分析和流式细胞术分析，研究了 BIBR1532 与放疗联合在 NSCLC 中的作用。测量细胞内脂质过氧化物、谷胱甘肽、丙二醛和铁的水平，作为铁死亡状态的指标。进行了体内和体外研究来检测抗肿瘤效果。
我们的研究结果表明，BIBR1532 与 RT 的联合使用显著增强了体内和体外 cGAS-STING 通路的激活，从而促进了有效的抗肿瘤免疫反应。这种作用可以归因于两个关键过程。首先，电离辐射导致 DNA 双链断裂（DSBs），促使肿瘤来源的双链 DNA（dsDNA）释放到细胞质中。随后，BIBR1532 增强了 RT 后抗原呈递细胞对 dsDNA 的激活，并引发了 cGAS-STING 通路。其次，BIBR1532 增强了 NSCLC 对 RT 后的铁死亡反应，从而促进了不受控制的脂质过氧化和肿瘤细胞内活性氧（ROS）水平的升高。这最终导致线粒体应激和内源性线粒体 DNA（mtDNA）释放到细胞质中，从而促进了 STING 通路的激活和 I 型干扰素（IFN）相关适应性免疫反应的诱导。
这项研究强调了 BIBR1532 作为一种有效和安全的放射增敏剂和放射免疫治疗协同剂的潜力，为 NSCLC 的治疗提供了强有力的临床前研究证据。
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