| Autor: |
Alfred Zippelius, Petra Herzig, Heinz Läubli, Gieri Cathomas, Christian Klein, Marta Trüb, Franziska Uhlenbrock, Christina Claus, Martin Thelen, Marina Bacac, Maria Amann, Rosemarie Albrecht, Claudia Ferrara-Koller, Daniela Thommen, Sacha Rothschield, Spasenija Savic Prince, Kirsten D Mertz, Robert Rosenberg, Viola Heinzelmann-Schwarz, Mark Wiese, Didier Lardinois, Pablo Umana, Abhishek S Kashyap |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Journal for ImmunoTherapy of Cancer, Vol 8, Iss 2 (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2051-1426 |
| DOI: |
10.1136/jitc-2019-000238 |
| Popis: |
Background The 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.Methods We 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.Results Combination 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.Conclusions Our 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: |
Directory of Open Access Journals |
| Externí odkaz: |
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