PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way
Background Various tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to impro...
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BMJ Publishing Group
2022-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/10/e004590.full |
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| author | Wei Huang Ji Zhou Jia Li Yakun Wan Chao Hu Meng Liu Pan Xu Feng Tang Jianhua Sun Xiaolu Yu Yiru Long Binfan Chen Yongliang Tong Mengwen Shan Xiaomin Jia Henglei Lu Runqiu Chen Jin Ren Guangyi Jin Likun Gong |
| author_facet | Wei Huang Ji Zhou Jia Li Yakun Wan Chao Hu Meng Liu Pan Xu Feng Tang Jianhua Sun Xiaolu Yu Yiru Long Binfan Chen Yongliang Tong Mengwen Shan Xiaomin Jia Henglei Lu Runqiu Chen Jin Ren Guangyi Jin Likun Gong |
| author_sort | Wei Huang |
| collection | DOAJ |
| description | Background Various tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to improve efficacy for anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on the PD-L1 nanobodies and TLR7 agonist we developed.Methods PD-L1 nanobodies were obtained by phage display screening and identified through T-cell activation bioassay, in vivo imaging and quantitative biodistribution study. Immune activation and PD-L1-inducing of TLR7 agonists were evaluated in diverse innate cell models. We constructed PD-L1/TLR7 dual-targeting NDCs by chemically coupling PD-L1 nanobodies and TLR7 agonists. The antitumor effect was evaluated via several murine or humanized solid tumor models. Immunophenotyping, immune cell depletion, tumor rechallenge, RNA sequencing and PD-L1-deficient models were combined to determine the mechanism for NDCs function. The dynamics of the in vivo behaviors of NDCs were assessed based on multiorgan changes in PD-L1 levels.Results The screened PD-L1 nanobodies were characterized as tumor-targeting and alleviated T-cell immunosuppression. The TLR7 agonists induced broad innate immune responses and intratumoral PD-L1 expression on antigen-presenting cells (APCs), and its antitumor effect was dependent on intratumoral delivery. The combination of TLR7 agonists and PD-L1 nanobodies activated both innate and adaptive immunity and upregulated PD-L1-related signaling pathways. After coupling to form dual-targeting NDCs, TLR7 agonists and PD-L1 nanobodies exerted synergistic antitumor effects and safety in either ‘hot’ or ‘cold’ tumor and early or advanced tumor models, reshaped the tumor immune microenvironment and induced antitumor immune memory. CD8+ T cells and natural killer cells were the main effector cells for NDCs to function. NDCs can promote PD-L1 expression on intratumoral APCs and tumor cells, and subsequently achieve targeted enrichment in tumors. Moreover, the efficacy of NDCs is biased toward dependence on host expression of PD-L1.Conclusions The novel PD-L1/TLR7 dual-targeting NDC exhibited potent efficacy against heterogeneous tumors through orchestrating innate and adaptive immunity, which could act as a promising strategy to improve ICB therapy and shows prospects for clinical development. |
| format | Article |
| id | doaj-art-9785092a1d2a49138eedb944273457b5 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-9785092a1d2a49138eedb944273457b52025-02-03T04:55:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-10-01101010.1136/jitc-2022-004590PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent wayWei Huang0Ji Zhou1Jia Li2Yakun Wan3Chao Hu4Meng Liu5Pan Xu6Feng Tang7Jianhua Sun8Xiaolu Yu9Yiru Long10Binfan Chen11Yongliang Tong12Mengwen Shan13Xiaomin Jia14Henglei Lu15Runqiu Chen16Jin Ren17Guangyi Jin18Likun Gong192 Health Management Center, First Affiliated Hospital, University of South China, Hengyang, Hunan, China1 Department of Vascular Neurosurgery, New Era Stroke Care and Research Institute, the PLA Rocket Force General Hospital, Beijing, ChinaDepartment of Neurology, Wuhan No. 1 Hospital, Wuhan, Hubei, China3 Shanghai Novamab Biopharmaceuticals Co., Ltd, Shanghai, ChinaState Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, ChinaPeking University Institute for Global Health and Development, Beijing, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaWuhan Children`s Hospital, Wuhan, Hubei, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaKey Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaInternational Cancer Center, Nation-Regional Engineering Lab for Synthetic Biology of Medicine, School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaBackground Various tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to improve efficacy for anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on the PD-L1 nanobodies and TLR7 agonist we developed.Methods PD-L1 nanobodies were obtained by phage display screening and identified through T-cell activation bioassay, in vivo imaging and quantitative biodistribution study. Immune activation and PD-L1-inducing of TLR7 agonists were evaluated in diverse innate cell models. We constructed PD-L1/TLR7 dual-targeting NDCs by chemically coupling PD-L1 nanobodies and TLR7 agonists. The antitumor effect was evaluated via several murine or humanized solid tumor models. Immunophenotyping, immune cell depletion, tumor rechallenge, RNA sequencing and PD-L1-deficient models were combined to determine the mechanism for NDCs function. The dynamics of the in vivo behaviors of NDCs were assessed based on multiorgan changes in PD-L1 levels.Results The screened PD-L1 nanobodies were characterized as tumor-targeting and alleviated T-cell immunosuppression. The TLR7 agonists induced broad innate immune responses and intratumoral PD-L1 expression on antigen-presenting cells (APCs), and its antitumor effect was dependent on intratumoral delivery. The combination of TLR7 agonists and PD-L1 nanobodies activated both innate and adaptive immunity and upregulated PD-L1-related signaling pathways. After coupling to form dual-targeting NDCs, TLR7 agonists and PD-L1 nanobodies exerted synergistic antitumor effects and safety in either ‘hot’ or ‘cold’ tumor and early or advanced tumor models, reshaped the tumor immune microenvironment and induced antitumor immune memory. CD8+ T cells and natural killer cells were the main effector cells for NDCs to function. NDCs can promote PD-L1 expression on intratumoral APCs and tumor cells, and subsequently achieve targeted enrichment in tumors. Moreover, the efficacy of NDCs is biased toward dependence on host expression of PD-L1.Conclusions The novel PD-L1/TLR7 dual-targeting NDC exhibited potent efficacy against heterogeneous tumors through orchestrating innate and adaptive immunity, which could act as a promising strategy to improve ICB therapy and shows prospects for clinical development.https://jitc.bmj.com/content/10/10/e004590.full |
| spellingShingle | Wei Huang Ji Zhou Jia Li Yakun Wan Chao Hu Meng Liu Pan Xu Feng Tang Jianhua Sun Xiaolu Yu Yiru Long Binfan Chen Yongliang Tong Mengwen Shan Xiaomin Jia Henglei Lu Runqiu Chen Jin Ren Guangyi Jin Likun Gong PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way Journal for ImmunoTherapy of Cancer |
| title | PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way |
| title_full | PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way |
| title_fullStr | PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way |
| title_full_unstemmed | PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way |
| title_short | PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way |
| title_sort | pd l1 tlr7 dual targeting nanobody drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host expressed pd l1 bias dependent way |
| url | https://jitc.bmj.com/content/10/10/e004590.full |
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