Cancer Res Treat.  2020 Apr;52(2):406-418. 10.4143/crt.2019.296.

Apatinib Combined with Local Irradiation Leads to Systemic TumorControl via Reversal of Immunosuppressive Tumor Microenvironmentin Lung Cancer

Affiliations
  • 1Department of Oncology, The Aliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
  • 2Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, China
  • 3Department of Clinical Pharmacology, The Aliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China
  • 4Medical Imaging Faculty of Xuzhou Medical University, Xuzhou, China

Abstract

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.

Keyword

Apatinib; Stereotactic ablative radiotherapy; Anti-angiogenesis; PD-L1; Abscopal effect
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