Cheng-Liang Kuo1, Han-Yu Chou1, Hui-Wen Lien1,2, Chia-An Yeh1,3, Jing-Rong Wang2, Chung-Hsing Chen1, Chi-Chen Fan4, Chih-Ping Hsu3, Ting-Yu Kao3, Tai-Ming Ko2,5, Alan Yueh-Luen Lee6,7,8,9. 1. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan. 2. Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, 300, Taiwan. 3. Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu, 300, Taiwan. 4. Department of research and development, Marker Exploration Corporation, Taipei, Taiwan. 5. Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan. 6. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan. alanylee@nhri.edu.tw. 7. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan. alanylee@nhri.edu.tw. 8. Department of Life Sciences, College of Life Science, National Central University, Taoyuan, 32031, Taiwan. alanylee@nhri.edu.tw. 9. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. alanylee@nhri.edu.tw.
Abstract
BACKGROUND: Immunotherapy is an emerging cancer therapy with potential great success; however, immune checkpoint inhibitor (e.g., anti-PD-1) has response rates of only 10-30% in solid tumor because of the immunosuppressive tumor microenvironment (TME). This affliction can be solved by vascular normalization and TME reprogramming. METHODS: By using the single-cell RNA sequencing (scRNAseq) approach, we tried to find out the reprogramming mechanism that the Fc-VEGF chimeric antibody drug (Fc-VFD) enhances immune cell infiltration in the TME. RESULTS: In this work, we showed that Fc-VEGF121-VEGF165 (Fc-VEGF chimeric antibody drug, Fc-VFD) arrests excess angiogenesis and tumor growth through vascular normalization using in vitro and in vivo studies. The results confirmed that the treatment of Fc-VFD increases immune cell infiltration including cytotoxic T, NK, and M1-macrophages cells. Indeed, Fc-VFD inhibits Lon-induced M2 macrophages polarization that induces angiogenesis. Furthermore, Fc-VFD inhibits the secretion of VEGF-A, IL-6, TGF-β, or IL-10 from endothelial, cancer cells, and M2 macrophage, which reprograms immunosuppressive TME. Importantly, Fc-VFD enhances the synergistic effect on the combination immunotherapy with anti-PD-L1 in vivo. CONCLUSIONS: In short, Fc-VFD fusion normalizes intratumor vasculature to reprogram the immunosuppressive TME and enhance cancer immunotherapy.
BACKGROUND: Immunotherapy is an emerging cancer therapy with potential great success; however, immune checkpoint inhibitor (e.g., anti-PD-1) has response rates of only 10-30% in solid tumor because of the immunosuppressive tumor microenvironment (TME). This affliction can be solved by vascular normalization and TME reprogramming. METHODS: By using the single-cell RNA sequencing (scRNAseq) approach, we tried to find out the reprogramming mechanism that the Fc-VEGF chimeric antibody drug (Fc-VFD) enhances immune cell infiltration in the TME. RESULTS: In this work, we showed that Fc-VEGF121-VEGF165 (Fc-VEGF chimeric antibody drug, Fc-VFD) arrests excess angiogenesis and tumor growth through vascular normalization using in vitro and in vivo studies. The results confirmed that the treatment of Fc-VFD increases immune cell infiltration including cytotoxic T, NK, and M1-macrophages cells. Indeed, Fc-VFD inhibits Lon-induced M2 macrophages polarization that induces angiogenesis. Furthermore, Fc-VFD inhibits the secretion of VEGF-A, IL-6, TGF-β, or IL-10 from endothelial, cancer cells, and M2 macrophage, which reprograms immunosuppressive TME. Importantly, Fc-VFD enhances the synergistic effect on the combination immunotherapy with anti-PD-L1 in vivo. CONCLUSIONS: In short, Fc-VFD fusion normalizes intratumor vasculature to reprogram the immunosuppressive TME and enhance cancer immunotherapy.