Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University/Yunnan Cancer Hospital, PR China; Key Laboratory of Lung Cancer Research of Yunnan Province, The Third Affiliated Hospital of Kunming Medical University/Yunnan Cancer Center, Kunming, Yunnan 650118, PR China.
Department of Radiation Oncology, The Third Affiliated Hospital of Kunming Medical University/Yunnan Cancer Hospital, PR China.
Life Sci. 2021 Jul 15;277:119594. doi: 10.1016/j.lfs.2021.119594. Epub 2021 May 11.
Ionizing radiation (IR) can induce local and systemic antitumour immune responses to some degree and augment immunotherapeutic efficacy. IR may also increase residual tumour cell invasion and elicit immunosuppression in the tumour microenvironment (TME). It remains poorly understand, whether IR leads to immune negative response or invasive capacity increases in lung adenocarcinoma (LAC).
RNA interference (RNAi) was used to silence pituitary tumour-transforming gene-1 (PTTG1) and SMAD3 expression in LAC cells. A coculture system of tumour cells and PBMCs was constructed. Cells were exposed to different doses (0, 4 and 8 Gy) of X-ray irradiation. Flow cytometric analysis and Transwell assays were applied. An orthotopic Lewis lung cancer (LLC) mouse tumour model was established. Bioluminescence imaging (BLI) was used. LLC tumours were exposed to a single 15 Gy dose of X-ray irradiation.
PTTG1 knockdown reinforced the inhibitory effect of IR on the invasive ability of A549 cells and enhanced the antitumour T cell immunity induced by IR via the transforming growth factor-β1 (TGF-β1)/SMAD3 pathway. Positive antitumour immune response and immunosuppression were simultaneously triggered by a single 15 Gy dose of local tumour irradiation. PTTG1 knockdown weakened invasive capacity and promoted the immune response balance induced by IR to tilt towards active immunity, which contributed to reduce metastasis and prolonged overall survival (OS) in orthotopic LLC tumour-bearing mouse.
Targeted blockade of PTTG1 and the TGF-β1/SMAD3 pathway may ameliorate the immunosuppressive TME and enhance the systemic antitumour immune response induced by a single high-dose IR treatment.
电离辐射（IR）在一定程度上可以诱导局部和全身抗肿瘤免疫反应，并增强免疫治疗效果。IR 也可能增加肿瘤微环境（TME）中残留肿瘤细胞的侵袭，并引发免疫抑制。目前尚不清楚 IR 是否会导致肺腺癌（LAC）产生免疫负性反应或侵袭能力增加。
使用 RNA 干扰（RNAi）沉默 LAC 细胞中的垂体肿瘤转化基因-1（PTTG1）和 SMAD3 的表达。构建肿瘤细胞和 PBMC 的共培养体系。将细胞暴露于不同剂量（0、4 和 8 Gy）的 X 射线照射下。采用流式细胞术分析和 Transwell 测定法。建立原位 Lewis 肺癌（LLC）小鼠肿瘤模型。采用生物发光成像（BLI）。将 LLC 肿瘤暴露于单次 15 Gy X 射线照射。
PTTG1 敲低增强了 IR 对 A549 细胞侵袭能力的抑制作用，并通过转化生长因子-β1（TGF-β1）/SMAD3 通路增强了 IR 诱导的抗肿瘤 T 细胞免疫。单次局部肿瘤照射会同时引发积极的抗肿瘤免疫反应和免疫抑制。PTTG1 敲低削弱了侵袭能力，并促进了 IR 诱导的免疫反应平衡向主动免疫倾斜，有助于减少转移并延长荷瘤小鼠的总生存期（OS）。
靶向阻断 PTTG1 和 TGF-β1/SMAD3 通路可能改善免疫抑制性 TME，并增强单次高剂量 IR 治疗诱导的全身抗肿瘤免疫反应。
