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Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer

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...

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Autores principales: Trüb, Marta, Uhlenbrock, Franziska, Claus, Christina, Herzig, Petra, Thelen, Martin, Karanikas, Vaios, Bacac, Marina, Amann, Maria, Albrecht, Rosemarie, Ferrara-Koller, Claudia, Thommen, Daniela, Rothschield, Sacha, Savic Prince, Spasenija, Mertz, Kirsten D, Cathomas, Gieri, Rosenberg, Robert, Heinzelmann-Schwarz, Viola, Wiese, Mark, Lardinois, Didier, Umana, Pablo, Klein, Christian, Laubli, Heinz, Kashyap, Abhishek S, Zippelius, Alfred
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333869/
https://www.ncbi.nlm.nih.gov/pubmed/32616554
http://dx.doi.org/10.1136/jitc-2019-000238
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author Trüb, Marta
Uhlenbrock, Franziska
Claus, Christina
Herzig, Petra
Thelen, Martin
Karanikas, Vaios
Bacac, Marina
Amann, Maria
Albrecht, Rosemarie
Ferrara-Koller, Claudia
Thommen, Daniela
Rothschield, Sacha
Savic Prince, Spasenija
Mertz, Kirsten D
Cathomas, Gieri
Rosenberg, Robert
Heinzelmann-Schwarz, Viola
Wiese, Mark
Lardinois, Didier
Umana, Pablo
Klein, Christian
Laubli, Heinz
Kashyap, Abhishek S
Zippelius, Alfred
author_facet Trüb, Marta
Uhlenbrock, Franziska
Claus, Christina
Herzig, Petra
Thelen, Martin
Karanikas, Vaios
Bacac, Marina
Amann, Maria
Albrecht, Rosemarie
Ferrara-Koller, Claudia
Thommen, Daniela
Rothschield, Sacha
Savic Prince, Spasenija
Mertz, Kirsten D
Cathomas, Gieri
Rosenberg, Robert
Heinzelmann-Schwarz, Viola
Wiese, Mark
Lardinois, Didier
Umana, Pablo
Klein, Christian
Laubli, Heinz
Kashyap, Abhishek S
Zippelius, Alfred
author_sort Trüb, Marta
collection PubMed
description 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.
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spelling pubmed-73338692020-07-07 Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer Trüb, Marta Uhlenbrock, Franziska Claus, Christina Herzig, Petra Thelen, Martin Karanikas, Vaios Bacac, Marina Amann, Maria Albrecht, Rosemarie Ferrara-Koller, Claudia Thommen, Daniela Rothschield, Sacha Savic Prince, Spasenija Mertz, Kirsten D Cathomas, Gieri Rosenberg, Robert Heinzelmann-Schwarz, Viola Wiese, Mark Lardinois, Didier Umana, Pablo Klein, Christian Laubli, Heinz Kashyap, Abhishek S Zippelius, Alfred J Immunother Cancer Clinical/Translational Cancer Immunotherapy 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. BMJ Publishing Group 2020-07-02 /pmc/articles/PMC7333869/ /pubmed/32616554 http://dx.doi.org/10.1136/jitc-2019-000238 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Clinical/Translational Cancer Immunotherapy
Trüb, Marta
Uhlenbrock, Franziska
Claus, Christina
Herzig, Petra
Thelen, Martin
Karanikas, Vaios
Bacac, Marina
Amann, Maria
Albrecht, Rosemarie
Ferrara-Koller, Claudia
Thommen, Daniela
Rothschield, Sacha
Savic Prince, Spasenija
Mertz, Kirsten D
Cathomas, Gieri
Rosenberg, Robert
Heinzelmann-Schwarz, Viola
Wiese, Mark
Lardinois, Didier
Umana, Pablo
Klein, Christian
Laubli, Heinz
Kashyap, Abhishek S
Zippelius, Alfred
Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
title Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
title_full Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
title_fullStr Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
title_full_unstemmed Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
title_short Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
title_sort fibroblast activation protein-targeted-4-1bb ligand agonist amplifies effector functions of intratumoral t cells in human cancer
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333869/
https://www.ncbi.nlm.nih.gov/pubmed/32616554
http://dx.doi.org/10.1136/jitc-2019-000238
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