Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity.

Autor:	Fernandez-Rodriguez L; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland., Cianciaruso C; Department of Pathology and Immunology, University of Geneva, Geneve, Switzerland.; AGORA Cancer Research Center, Lausanne, Switzerland.; Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA., Bill R; Department of Pathology and Immunology, University of Geneva, Geneve, Switzerland.; AGORA Cancer Research Center, Lausanne, Switzerland.; Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA., Trefny MP; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland., Klar R; Secarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, Germany., Kirchhammer N; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland., Buchi M; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland., Festag J; Secarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, Germany., Michel S; Secarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, Germany., Kohler RH; Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA., Jones E; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland., Maaske A; Secarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, Germany., Vom Berg J; Institute of Laboratory Animal Science, University of Zurich, Zürich, Switzerland., Kobold S; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU, Munich, Germany.; German Center for Lung Research (DZL), German Center for Translational Cancer Research (DKTK), partner site Munich, Munich, Germany., Kashyap AS; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland., Jaschinski F; Secarna Pharmaceuticals GmbH & Co KG, Planegg Martinsried, Germany., Dixon KO; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland., Pittet MJ; Department of Pathology and Immunology, University of Geneva, Geneve, Switzerland mikael.pittet@unige.ch alfred.zippelius@usb.ch.; AGORA Cancer Research Center, Lausanne, Switzerland.; Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, USA.; Ludwig Institute for Cancer Research Lausanne Branch, Lausanne, Switzerland., Zippelius A; Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland mikael.pittet@unige.ch alfred.zippelius@usb.ch.; Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 May; Vol. 11 (5).
DOI:	10.1136/jitc-2023-006714
Abstrakt:	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. Competing Interests: Competing interests: AZ received consulting/advisor fees from BMS, MSD, Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma, and Hookipa, and maintains further non-commercial research agreements with Secarna, Hookipa, and Beyondsprings. MP has served as a consultant for Aileron Therapeutics, AstraZeneca, Cygnal Therapeutics, Elstar Therapeutics, ImmuneOncia, KSQ Therapeutics, Merck, Siamab Therapeutics, and Third Rock Ventures. The wife of RB is an employee and shareholder of CSL Behring and RB received speakers fee from Janssen. RHK, JF, AM, and FJ are employed by Secarna. CC is currently employed by Idorsia Pharmaceuticals. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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