Lan Yanli, Pi Wenhu, Zhou Zhangjie, Meng Yinnan, Xu Yixiu, Xia Xinhang, Yang HaiHua, Spring Kong Feng-Ming
Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province 317000, China; The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui City People's Hospital, Department of Oncology, Lishui 323000, Zhejiang Province, China.
Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang Province 317000, China.
Int Immunopharmacol. 2023 Nov;124(Pt B):110956. doi: 10.1016/j.intimp.2023.110956. Epub 2023 Sep 24.
Radiotherapy (RT) is the mainstay treatment modality for lung cancer. We recently reported that conventionally fractionated radiotherapy (CRT) with daily fractionation of 2Gy significantly increased the activity of indoleamine 2,3-dioxygenase (IDO1), a known immune checkpoint, which predicted poorer long-term survival in patients with non-small cell lung cancer (NSCLC), while stereotactic body radiotherapy (SBRT) using fractionation size of 10Gy did not increase IDO1 activity and had better survival. Here we hypothesized that the hypofractionated SBRT kind of dose fraction stimulates host antitumor immunity via downregulating IDO1 in which CRT could not. We tested this hypothesis in vitro and in vivo using 10Gyx1 and 2Gyx8 fractionations in the laboratory. The results demonstrated that, although there was an initial downregulation after RT, the expression of IDO1 was ultimately upregulated by both fractionation regimens. The 10Gyx1 regimen had minimum upregulation, while the 2Gyx8 regimen significantly increased in IDO1 expression which was positively correlated with the elevated expressions of p-NF-κB and COX2. Pharmacological inhibition of COX2 abolished RT-induced IDO1 expression. Furthermore, the IDO1 inhibitor, D-1-methyl-tryptophan (D-1MT), exerted RT-related tumor-killing effects in the NSCLC cell lines and mouse models. These findings suggest that, in addition to being an immune suppressor, IDO1 may serve as an adaptive resistance factor in RT. Furthermore, an unappreciated mechanism may exist, where a larger fraction size might be superior to conventional sizes in cancer treatment. This study may provide a rationale for future research in using IDO1 as a biomarker to personalize RT dose fractionation and COX2 inhibitor to decrease radiation immune suppression from CRT.
放射治疗（RT）是肺癌的主要治疗方式。我们最近报道，每日分割剂量为2Gy的常规分割放疗（CRT）显著增加了吲哚胺2,3-双加氧酶（IDO1）的活性，IDO1是一种已知的免疫检查点，这预示着非小细胞肺癌（NSCLC）患者的长期生存率较差，而采用10Gy分割剂量的立体定向体部放疗（SBRT）并未增加IDO1活性，且生存率更高。在此，我们假设大分割SBRT这种剂量分割方式可通过下调IDO1来刺激宿主抗肿瘤免疫，而CRT则无法做到。我们在实验室中使用10Gyx1和2Gyx8分割方案在体外和体内对这一假设进行了验证。结果表明，尽管放疗后IDO1最初有下调，但两种分割方案最终均使IDO1表达上调。10Gyx1方案的上调幅度最小，而2Gyx8方案使IDO1表达显著增加，且与p-NF-κB和COX2表达升高呈正相关。COX2的药理抑制作用消除了放疗诱导的IDO1表达。此外，IDO1抑制剂D-1-甲基色氨酸（D-1MT）在NSCLC细胞系和小鼠模型中发挥了与放疗相关的肿瘤杀伤作用。这些发现表明，IDO1除作为免疫抑制因子外，可能还作为放疗中的一种适应性抵抗因子。此外，可能存在一种未被认识的机制，即更大的分割剂量在癌症治疗中可能优于传统剂量。本研究可能为未来将IDO1用作生物标志物以实现放疗剂量分割个体化以及使用COX2抑制剂减少CRT引起的放射免疫抑制的研究提供理论依据。
