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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2020
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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. |
format | Online Article Text |
id | pubmed-7333869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
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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