Trub, Marta, Uhlenbrock, Franziska, Claus, Christina, Herzig, Petra, Thelen, Martin ORCID: 0000-0002-2785-9726, Karanikas, Vaios, Bacac, Marina, Amann, Maria, Albrecht, Rosemarie, Ferrara-Koller, Claudia, Thommen, Daniela, Rothschield, Sacha, Prince, Spasenija Savic, Mertz, Kirsten D., Cathomas, Gieri, Rosenberg, Robert, Heinzelmann-Schwarz, Viola, Wiese, Mark, Lardinois, Didier, Umana, Pablo, Klein, Christian ORCID: 0000-0001-7594-7280, Laubli, Heinz, Kashyap, Abhishek S. and Zippelius, Alfred (2020). Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. J. Immunother. Cancer, 8 (2). LONDON: BMJ PUBLISHING GROUP. ISSN 2051-1426

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Trub, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhlenbrock, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claus, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herzig, PetraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, MartinUNSPECIFIEDorcid.org/0000-0002-2785-9726UNSPECIFIED
Karanikas, VaiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bacac, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amann, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Albrecht, RosemarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferrara-Koller, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thommen, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rothschield, SachaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prince, Spasenija SavicUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertz, Kirsten D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cathomas, GieriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenberg, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinzelmann-Schwarz, ViolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiese, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lardinois, DidierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Umana, PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, ChristianUNSPECIFIEDorcid.org/0000-0001-7594-7280UNSPECIFIED
Laubli, HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kashyap, Abhishek S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zippelius, AlfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-350096
DOI: 10.1136/jitc-2019-000238
Journal or Publication Title: J. Immunother. Cancer
Volume: 8
Number: 2
Date: 2020
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2051-1426
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
4-1BB; RECEPTOR; COSTIMULATION; PROLIFERATION; EXPRESSION; INTERLEUKIN-4; GLIOBLASTOMA; LYMPHOCYTES; EXHAUSTION; GROWTHMultiple languages
Oncology; ImmunologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/35009

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