2. Academic Validation
  3. Effect of radiation fractionation on IDO1 via the NF-κB/COX2 axis in non-small cell lung cancer

Effect of radiation fractionation on IDO1 via the NF-κB/COX2 axis in non-small cell lung cancer

  • Int Immunopharmacol. 2023 Sep 24;124(Pt B):110956. doi: 10.1016/j.intimp.2023.110956.
Yanli Lan 1,  Wenhu Pi 2,  Zhangjie Zhou 3,  Yinnan Meng 4,  DanMei 2,  Yixiu Xu 2,  Xinhang Xia 2,  WeiWang 2,  HaiHua Yang 5,  Feng-Ming Spring Kong 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui Municipal Central Hospital, Department of General Medicine, Lishui 323000, Zhejiang Province, China.
  • 4 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; Department of Clinical Oncology, Hong Kong University Shenzhen Hospital, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China.
  • 5 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. Electronic address: yhh93181@hotmail.com.
  • 6 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; Department of Clinical Oncology, Hong Kong University Shenzhen Hospital, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China. Electronic address: kong0001@hku.hk.
PMID: 37751656 DOI: 10.1016/j.intimp.2023.110956
Abstract

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.

Keywords

COX2; CRT; D-1MT; IDO1; NSCLC; SBRT.

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