Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
| Autor: | Daniela S. Thommen, Didier Lardinois, Pablo Umana, Mark Wiese, Vaios Karanikas, Kirsten D. Mertz, Martin Thelen, Christina Claus, Maria Amann, Viola Heinzelmann-Schwarz, Alfred Zippelius, Marina Bacac, Marta Trüb, Heinz Läubli, Gieri Cathomas, Christian Klein, Rosemarie Albrecht, Franziska Uhlenbrock, Petra Herzig, Abhishek S. Kashyap, Claudia Ferrara-Koller, Spasenija Savic Prince, Sacha Rothschield, Robert Rosenberg |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist tumors Cancer Research medicine.drug_class medicine.medical_treatment T cell Receptors Antigen T-Cell Transfection Proinflammatory cytokine immunology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Fibroblast activation protein alpha Neoplasms medicine Immunology and Allergy Humans RC254-282 Aged Pharmacology Clinical/Translational Cancer Immunotherapy business.industry CD137 Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunotherapy Fibroblasts 3. Good health 030104 developmental biology 4-1BB ligand medicine.anatomical_structure 4-1BB Ligand chemistry 030220 oncology & carcinogenesis oncology Cancer research Molecular Medicine business |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 8, Iss 2 (2020) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundThe costimulatory receptor 4-1BB (CD137, TNFRSF9) plays an important role in sustaining effective T cell immune responses and is investigated as target for cancer therapy. Systemic 4-1BB directed therapies elicit toxicity or low efficacy, which significantly hampered advancement of 4-1BB-based immunotherapy. Therefore, targeted delivery of 4-1BB agonist to the tumor side is needed for eliciting antitumor efficacy while avoiding systemic toxicity.MethodsWe analyzed the immunostimulatory properties of a fibroblast activation protein (FAP)-targeted 4-1BB agonist (FAP-4-1BBL) by assessing tumor-infiltrating lymphocytes’ (TIL) activity from patients with non-small cell lung cancer and epithelial ovarian cancer.ResultsCombination treatment with FAP-4-1BBL and T cell receptor stimulation by either anti-CD3 or T cell bispecific antibodies significantly enhanced TIL activation and effector functions, including T cell proliferation, secretion of proinflammatory cytokines and cytotoxicity. Notably, costimulation with FAP-4-1BBL led to de novo secretion of interleukin (IL)−13. This was associated with cytokine-mediated tumor cell apoptosis, which was partially dependent on IL-13 alpha 1/2 receptors and STAT6 phosphorylation.ConclusionsOur study provides mechanistic insights into T cell stimulation induced by FAP-4-1BBL in primary human tumors and supports the investigation of FAP-4-1BBL compound in early clinical trials. |
| Databáze: | OpenAIRE |
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