Apatinib Combined with Local Irradiation Leads to Systemic Tumor Control via Reversal of Immunosuppressive Tumor Microenvironment in Lung Cancer

Abstract

PurposeThis 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 MethodsLewis 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.ResultsFor 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.ConclusionOur results suggested that the tumor microenvironment could be managed with apatinib, which was effective in eliciting an abscopal effect induced by SABR.

Oridonin inhibits tumor angiogenesis and induces vessel normalization in experimental colon cancer

“…Hence, antiangiogenic therapy seems would be anticipated to render many chemoradiotherapy and immunotherapy schedules less effective. However, paradoxically, accumulated evidence suggest that antiangiogenic agents augment rather than weaken the anticancer effects of radiation or chemotherapy [12,13,14]. Fortunately, the proposition of the new concept that antiangiogenic therapy transiently normalizes abnormal tumor vasculature both structurally and functionally which providing a window of opportunity for enhancing the efficacy of chemotherapy or radiotherapy solves this contradiction well [15].…”

“…An increasing number of anti-angiogenesis Ivyspring International Publisher therapy has been extensively developed for cancer treatment, effectively suppressing tumor growth [9][10][11]. However, accumulating data reveal that anti-angiogenesis therapies destroy the delivery of oxygen and therapeutics dependent vasculatures can simultaneously potentiate the therapeutic effects of radiation and chemotherapy [12][13][14]. This seems paradoxical.…”

Local Destruction of Tumors and Systemic Immune Effects

“…Rejection immunity was investigated in relatively few studies and was seen in 4/6 studies after radiotherapy alone ( 39 , 158 , 168 , 175 , 200 , 201 ) and in 11/11 studies after combined treatment.…”

“…In contrast, CD8 levels rose in combination therapies regardless of the immunomodulating agent used. In the spleen, CD8 levels, as estimated by tumor antigen specific activity, were unchanged following radiotherapy alone and usually increased in combination with an immunostimulant ( 157 , 161 , 182 , 191 , 200 ). Radiotherapy alone did not usually affect tissue levels of CD8 in untreated tumors ( 160 , 161 , 172 , 176 , 195 , 196 , 198 – 200 , 214 , 215 ) but both an increase and a decrease have been reported ( 173 , 174 , 190 , 197 ).…”

“…In the spleen, CD8 levels, as estimated by tumor antigen specific activity, were unchanged following radiotherapy alone and usually increased in combination with an immunostimulant ( 157 , 161 , 182 , 191 , 200 ). Radiotherapy alone did not usually affect tissue levels of CD8 in untreated tumors ( 160 , 161 , 172 , 176 , 195 , 196 , 198 – 200 , 214 , 215 ) but both an increase and a decrease have been reported ( 173 , 174 , 190 , 197 ). Combination with immunotherapy, regardless of the type, always increased CD8 levels in untreated tumors in these studies.…”