Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China.
Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China.
Cancer Res Treat. 2020 Apr;52(2):406-418. doi: 10.4143/crt.2019.296. Epub 2019 Sep 3.
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.
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.
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.
Our results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.
本研究旨在通过逆转肺癌的免疫抑制肿瘤微环境，研究立体定向消融放疗（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）对肺癌的潜在全身抗肿瘤作用。
将 Lewis 肺癌细胞注射到 C57BL/6 小鼠的左后肢（原发性肿瘤；照射）和右后腹（继发性肿瘤；未照射）。当两个肿瘤长到可触及的大小时，将小鼠随机分为八组。这些组每天接受生理盐水或三种不同剂量的阿帕替尼（50mg/kg、150mg/kg 和 200mg/kg），连续 7 天，联合或不联合单次 15Gy 放疗治疗原发性肿瘤。进一步观察和监测小鼠的肿瘤生长/消退情况。
对于单次 15Gy 治疗方式，仅在原发性肿瘤中观察到肿瘤生长延迟。当联合 SABR 和阿帕替尼 200mg/kg 时，可观察到原发性和继发性肿瘤的生长均显著延迟，表明诱导了远隔效应。机制分析表明，程序性死亡配体 1 的表达随着 SABR 的增加而增加，而额外的阿帕替尼治疗则拮抗了这种增加。此外，当阿帕替尼与 SABR 联合使用时，免疫细胞的组成可以发生变化。更重要的是，这种双管齐下的方法可以引发肿瘤抗原特异性免疫反应，使小鼠对另一次肿瘤再挑战具有抗性，最终提高了长期生存率。
我们的结果表明，阿帕替尼可用于管理肿瘤微环境，它在诱导 SABR 引起的远隔效应方面是有效的。
