Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer.
- Trüb M Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
- Uhlenbrock F Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
- Claus C Roche Innovation Center Zurich, Schlieren, Switzerland.
- Herzig P Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
- Thelen M Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
- Karanikas V Roche Innovation Center Zurich, Schlieren, Switzerland.
- Bacac M Roche Innovation Center Zurich, Schlieren, Switzerland.
- Amann M Roche Innovation Center Zurich, Schlieren, Switzerland.
- Albrecht R Roche Innovation Center Zurich, Schlieren, Switzerland.
- Ferrara-Koller C Roche Innovation Center Zurich, Schlieren, Switzerland.
- Thommen D Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Rothschield S Medical Oncology, University Hospital Basel, Basel, Switzerland.
- Savic Prince S Institute of Pathology, University Hospital Basel, Basel, Switzerland.
- Mertz KD Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland.
- Cathomas G Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland.
- Rosenberg R Department of Surgery, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland.
- Heinzelmann-Schwarz V Department of Gynecology and Obstetrics, University Hospital Basel, Basel, Switzerland.
- Wiese M Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland.
- Lardinois D Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland.
- Umana P Roche Innovation Center Zurich, Schlieren, Switzerland.
- Klein C Roche Innovation Center Zurich, Schlieren, Switzerland.
- Laubli H Medical Oncology, University Hospital Basel, Basel, Switzerland.
- Kashyap AS Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
- Zippelius A Medical Oncology, University Hospital Basel, Basel, Switzerland alfred.zippelius@usb.ch.
- 2020-07-04
Published in:
- Journal for immunotherapy of cancer. - 2020
English
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1136/jitc-2019-000238
- PMID 32616554
- Persistent URL
- https://sonar.ch/global/documents/232590
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