Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer
Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer
复制标题
阿帕替尼联合局部放疗通过逆转肺癌免疫抑制肿瘤微环境实现全身肿瘤控制
DOI：
10.4143/crt.2019.296
复制
发表时间：
2020-04-01
影响因子：
4.6
通讯作者：
Jiang, Xiao-dong
中科院分区：
文献类型：
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作者：
Liang, Li-jun;Hu, Chen-xi;Jiang, Xiao-dong
目的探讨立体定向消融放疗（SABR）联合阿帕替尼（一种新型血管内皮生长因子受体2抑制剂）通过逆转免疫抑制肿瘤微环境对肺癌的潜在全身抗肿瘤作用。材料与方法将Lewis肺癌细胞注射于C57BL/6小鼠左后肢（原发肿瘤，放疗）和右侧（继发肿瘤，未放疗）。当两个肿瘤都长到可触摸的大小时，小鼠被随机分为八个治疗组。这些组每天接受生理盐水或三种不同剂量的阿帕替尼（50 mg/kg、150 mg/kg和200 mg/kg），连续7天，并联合单剂量15 Gy放疗或不针对原发肿瘤。进一步跟踪观察小鼠肿瘤生长/消退情况。结果在15 Gy单一模式下，仅在原发肿瘤处观察到肿瘤生长延迟。当SABR与阿帕替尼（200mg /kg）联合使用时，可明显抑制原发和继发肿瘤的生长，表明SABR具有体外作用。机制分析表明，程序性死亡配体1表达随着SABR的增加被额外的阿帕替尼治疗所抵消。此外，当阿帕替尼与SABR联合使用时，可以改变免疫细胞的组成。更重要的是，这种双管齐下的方法激发了肿瘤抗原特异性免疫反应，小鼠对另一次肿瘤再攻击产生了抗性，最终提高了长期生存率。结论阿帕替尼可有效调控肿瘤微环境，并可诱导SABR诱导的体外效应。
Purpose This study aimed to investigate the potential systemic antitumor effects of stereotactic ablative radiotherapy (SABR) and apatinib (a novel vascular endothelial growth factor receptor 2 inhibitor) via reversing the immunosuppressive tumor microenvironment for lung carcinoma. Materials and Methods Lewis lung cancer cells were injected into C57BL/6 mice in the left hindlimb (primary tumor; irradiated) and in the right flank (secondary tumor; nonirradiated). When both tumors grew to the touchable size, mice were randomly divided into eight treatment groups. These groups received normal saline or three distinct doses of apatinib (50 mg/kg, 150 mg/kg, and 200 mg/kg) daily for 7 days, in combination with a single dose of 15 Gy radiotherapy or not to the primary tumor. The further tumor growth/regression of mice were followed and observed. Results For the single 15 Gy modality, tumor growth delay could only be observed at the primary tumor. When combining SABR and apatinib 200 mg/kg, significant retardation of both primary and secondary tumor growth could be observed, indicated an abscopal effect was induced. Mechanism analysis suggested that programmed death-ligand 1 expression increased with SABR was counteract by additional apatinib therapy. Furthermore, when apatinib was combined with SABR, the composition of immune cells could be changed. More importantly, this two-pronged approach evoked tumor antigen–specific immune responses and the mice were resistant to another tumor rechallenge, finally, long-term survival was improved. Conclusion Our results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.