Huang Kevin Chih-Yang, Chiang Shu-Fen, Ke Tao-Wei, Chen Tsung-Wei, Hu Ching-Han, Yang Pei-Chen, Chang Hsin-Yu, Liang Ji-An, Chen William Tzu-Liang, Chao K S Clifford
Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung Taiwan.
Translation Research Core, China Medical University Hospital, China Medical University, Taichung Taiwan.
Oncoimmunology. 2021 Oct 21;10(1):1989790. doi: 10.1080/2162402X.2021.1989790. eCollection 2021.
Radiotherapy can boost the therapeutic response to immune checkpoint inhibitors (ICIs) by recruiting T lymphocytes and upregulating PD-L1 expression within the tumor microenvironment (TME). However, in some cases, tumor PD-L1 expression cannot be induced, even in the presence of abundant T lymphocytes, in locally advanced colorectal cancer patients who receive preoperative neoadjuvant concurrent chemoradiotherapy (CCRT). In this study, we found that promoter methylation is negatively correlated with tumor PD-L1 expression and is an independent biomarker for locally advanced colorectal cancer patients. methylation () was significantly associated with shorter disease-free survival (cg15837913 loci, = .0124). By multivariate Cox proportional hazards analyses including influent factors, was classified as an independent prognostic factor for poor 5-year DFS [cg15837913, hazard ratio: HR = 4.06, 95% CI = 1.407-11.716, = .01]. We found that the immunomodulatory agent DNA methyltransferase inhibitor (DNMTi) led to demethylation of the promoter and increased radiotherapy-induced PD-L1 upregulation interferon β (IFNβ). DNMTi not only induced tumor PD-L1 expression but increased the expression of immune-related genes as well as intratumoral T cell infiltration . Furthermore, DNMTi strongly enhanced the response to combined treatment with radiotherapy and anti-PD-L1 inhibitors, and prolonged survival in microsatellite stability (MSS) colorectal model. Therefore, DNMTi remodeled the tumor microenvironment to improve the effect of radiotherapy and anti-PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger immune responses, which may provide potential clinical benefits to colorectal cancer patients in the future.
放射治疗可通过募集T淋巴细胞和上调肿瘤微环境（TME）中的PD-L1表达来增强对免疫检查点抑制剂（ICI）的治疗反应。然而，在一些情况下，接受术前新辅助同步放化疗（CCRT）的局部晚期结直肠癌患者中，即使存在大量T淋巴细胞，肿瘤PD-L1表达也无法被诱导。在本研究中，我们发现启动子甲基化与肿瘤PD-L1表达呈负相关，并且是局部晚期结直肠癌患者的独立生物标志物。甲基化（）与无病生存期缩短显著相关（cg15837913位点，=0.0124）。通过包括影响因素的多变量Cox比例风险分析，被归类为5年无病生存期差的独立预后因素[cg15837913，风险比：HR=4.06，95%CI=1.407-11.716，=0.01]。我们发现免疫调节剂DNA甲基转移酶抑制剂（DNMTi）导致启动子去甲基化，并增加放疗诱导的PD-L1上调干扰素β（IFNβ）。DNMTi不仅诱导肿瘤PD-L1表达，还增加免疫相关基因的表达以及肿瘤内T细胞浸润。此外，DNMTi强烈增强了放疗和抗PD-L1抑制剂联合治疗的反应，并延长了微卫星稳定（MSS）结直肠癌模型的生存期。因此，DNMTi通过直接触发肿瘤PD-L1表达并引发更强的免疫反应来重塑肿瘤微环境，以改善放疗和抗PD-L1免疫治疗的效果，这可能在未来为结直肠癌患者提供潜在的临床益处。
