Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity
Background Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Her...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/5/e006714.full |
| _version_ | 1797741500652584960 |
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| author | Alfred Zippelius Mélanie Buchi Richard Klar Julia Festag Sven Michel Frank Jaschinski Sebastian Kobold Abhishek S Kashyap Johannes vom Berg Laura Fernandez-Rodriguez Chiara Cianciaruso Ruben Bill Marcel P Trefny Nicole Kirchhammer Rainer H Kohler Elham Jones Andre Maaske Karen O Dixon Mikael J Pittet |
| author_facet | Alfred Zippelius Mélanie Buchi Richard Klar Julia Festag Sven Michel Frank Jaschinski Sebastian Kobold Abhishek S Kashyap Johannes vom Berg Laura Fernandez-Rodriguez Chiara Cianciaruso Ruben Bill Marcel P Trefny Nicole Kirchhammer Rainer H Kohler Elham Jones Andre Maaske Karen O Dixon Mikael J Pittet |
| author_sort | Alfred Zippelius |
| collection | DOAJ |
| description | Background Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy.Methods We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor.Results IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development.Conclusions By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer. |
| first_indexed | 2024-03-12T14:28:24Z |
| format | Article |
| id | doaj.art-78cf6c8515374d7f847b8913a986bde6 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T14:28:24Z |
| publishDate | 2023-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-78cf6c8515374d7f847b8913a986bde62023-08-17T23:25:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-05-0111510.1136/jitc-2023-006714Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunityAlfred Zippelius0Mélanie Buchi1Richard Klar2Julia Festag3Sven Michel4Frank Jaschinski5Sebastian Kobold6Abhishek S Kashyap7Johannes vom Berg8Laura Fernandez-Rodriguez9Chiara Cianciaruso10Ruben Bill11Marcel P Trefny12Nicole Kirchhammer13Rainer H Kohler14Elham Jones15Andre Maaske16Karen O Dixon17Mikael J Pittet18Department of Medical Oncology, University Hospital Basel, Basel, SwitzerlandDepartment of Biomedicine, University of Basel and University Hospital of Basel, Basel, SwitzerlandSecarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, GermanySecarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, GermanySecarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, GermanySecarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, GermanyEinheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, GermanyDepartment of Biomedicine, University of Basel and University Hospital of Basel, Basel, SwitzerlandInstitute of Laboratory Animal Science, University of Zurich, Schlieren, SwitzerlandDepartment of Biomedicine, University of Basel and University Hospital of Basel, Basel, SwitzerlandDepartment of Pathology and Immunology, University of Geneva, Geneve, SwitzerlandDepartment of Pathology and Immunology, University of Geneva, Geneve, SwitzerlandDepartment of Biomedicine, University of Basel and University Hospital of Basel, Basel, SwitzerlandDepartment of Biomedicine, University of Basel and University Hospital of Basel, Basel, SwitzerlandCenter for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USADepartment of Biomedicine, University of Basel and University Hospital of Basel, Basel, SwitzerlandSecarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, GermanyDepartment of Biomedicine, University of Basel and University Hospital of Basel, Basel, SwitzerlandDepartment of Pathology and Immunology, University of Geneva, Geneve, SwitzerlandBackground Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy.Methods We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor.Results IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3, a transcription factor required for DC development.Conclusions By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.https://jitc.bmj.com/content/11/5/e006714.full |
| spellingShingle | Alfred Zippelius Mélanie Buchi Richard Klar Julia Festag Sven Michel Frank Jaschinski Sebastian Kobold Abhishek S Kashyap Johannes vom Berg Laura Fernandez-Rodriguez Chiara Cianciaruso Ruben Bill Marcel P Trefny Nicole Kirchhammer Rainer H Kohler Elham Jones Andre Maaske Karen O Dixon Mikael J Pittet Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity Journal for ImmunoTherapy of Cancer |
| title | Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity |
| title_full | Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity |
| title_fullStr | Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity |
| title_full_unstemmed | Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity |
| title_short | Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity |
| title_sort | dual tlr9 and pd l1 targeting unleashes dendritic cells to induce durable antitumor immunity |
| url | https://jitc.bmj.com/content/11/5/e006714.full |
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