Jing Wu1, Xiaogang Zhao2, Qifeng Sun3, Yunfeng Jiang4, Weiquan Zhang2, Junwen Luo2, Yixin Li5. 1. Department of Pharmacy, The Second Hospital of Shandong University, Jinan, China; Key Laboratory of Chest Cancer, Shandong University,Jinan, China. 2. Department of Thoracic Surgery, The Second Hospital of Shandong University, Jinan, China; Key Laboratory of Chest Cancer, Shandong University,Jinan, China. 3. Department of Thoracic Surgery, Shandong Provincial Hospital, Jinan, China. 4. Department of Thoracic Surgery, YantaiYuhuangding Hospital, Yantai, China. 5. Key Laboratory of Chest Cancer, Shandong University,Jinan, China; Department of Medical Imaging, The Second Hospital of Shandong University, Jinan, China. Electronic address: liyixinsdey@126.com.
Abstract
BACKGROUND: Immunotherapy has been shown to be effective as a first-line treatment option for non-small cell lung cancer (NSCLC) patients. Unfortunately, it has failed to acquire an anticipant anti-tumour effect for relatively lower clinical benefit rates. It is therefore important to identify novel strategies for improving immunotherapy. Endostar is a novel recombinant human endostatin that exerts its anti-angiogenic effects via vascular endothelial growth factor (VEGF)-related signalling pathways. Anti-programmed death receptor 1 (PD-1) antibody is an immune checkpoint inhibitor that was developed to stimulate the immune system. In this study, the synergy of PD-1 blockade and endostar was assessed in a lung carcinoma mouse model. METHODS: Lewis lung carcinoma (LLC)-bearing mice were randomly assigned into three groups: controls, anti-PD-1 and anti-PD-1+endostar. The levels of cytokines such as interleukin (IL)-17, transforming growth factor-β1 (TGF-β1) and interferon-γ (IFN-γ) were measured with enzyme-linked immune sorbent assay (ELISA). The expression of VEGF, CD34 and CD31 was assessed with immunohistochemistry (IHC). The proportion of mature dendritic cells (mDC) and myeloid-derived suppressor cells (MDSC) was analysed with flow cytometry. The major proteins in PI3K/AKT/mTOR and autophagy were quantified with Western blot. RESULTS: Anti-PD-1 combined with endostar dramatically suppressed tumour growth in LLC mouse models. This synergistic effect resulted in decreased pro-inflammatory cytokine IL-17 and immunosuppressive factor TGF-β1 levels, increased IFN-γ secretion, reduced myeloid-derived suppressor cell (MDSC) accumulation, and reversed CD8 + T cell suppression. The expression of VEGF, CD34 and CD31 was significantly down-regulated, while tumour cell apoptosis and PI3K/AKT/mTOR-mediated autophagy was up-regulated. CONCLUSION: The combination of anti-PD-1 and endostar has a remarkably synergic effect on LLC tumour growth by means of improving the tumour microenvironment and activating autophagy.
BACKGROUND: Immunotherapy has been shown to be effective as a first-line treatment option for non-small cell lung cancer (NSCLC) patients. Unfortunately, it has failed to acquire an anticipant anti-tumour effect for relatively lower clinical benefit rates. It is therefore important to identify novel strategies for improving immunotherapy. Endostar is a novel recombinant humanendostatin that exerts its anti-angiogenic effects via vascular endothelial growth factor (VEGF)-related signalling pathways. Anti-programmed death receptor 1 (PD-1) antibody is an immune checkpoint inhibitor that was developed to stimulate the immune system. In this study, the synergy of PD-1 blockade and endostar was assessed in a lung carcinomamouse model. METHODS:Lewis lung carcinoma (LLC)-bearing mice were randomly assigned into three groups: controls, anti-PD-1 and anti-PD-1+endostar. The levels of cytokines such as interleukin (IL)-17, transforming growth factor-β1 (TGF-β1) and interferon-γ (IFN-γ) were measured with enzyme-linked immune sorbent assay (ELISA). The expression of VEGF, CD34 and CD31 was assessed with immunohistochemistry (IHC). The proportion of mature dendritic cells (mDC) and myeloid-derived suppressor cells (MDSC) was analysed with flow cytometry. The major proteins in PI3K/AKT/mTOR and autophagy were quantified with Western blot. RESULTS: Anti-PD-1 combined with endostar dramatically suppressed tumour growth in LLCmouse models. This synergistic effect resulted in decreased pro-inflammatory cytokine IL-17 and immunosuppressive factor TGF-β1 levels, increased IFN-γ secretion, reduced myeloid-derived suppressor cell (MDSC) accumulation, and reversed CD8 + T cell suppression. The expression of VEGF, CD34 and CD31 was significantly down-regulated, while tumour cell apoptosis and PI3K/AKT/mTOR-mediated autophagy was up-regulated. CONCLUSION: The combination of anti-PD-1 and endostar has a remarkably synergic effect on LLC tumour growth by means of improving the tumour microenvironment and activating autophagy.