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Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer.
J Immunother Cancer. 2020 Jul; 8(2)JI

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.

Authors+Show Affiliations

Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.Roche Innovation Center Zurich, Schlieren, Switzerland.Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.Roche Innovation Center Zurich, Schlieren, Switzerland.Roche Innovation Center Zurich, Schlieren, Switzerland.Roche Innovation Center Zurich, Schlieren, Switzerland.Roche Innovation Center Zurich, Schlieren, Switzerland.Roche Innovation Center Zurich, Schlieren, Switzerland.Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.Medical Oncology, University Hospital Basel, Basel, Switzerland.Institute of Pathology, University Hospital Basel, Basel, Switzerland.Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland.Institute of Pathology, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland.Department of Surgery, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland.Department of Gynecology and Obstetrics, University Hospital Basel, Basel, Switzerland.Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland.Division of Thoracic Surgery, University Hospital Basel, Basel, Switzerland.Roche Innovation Center Zurich, Schlieren, Switzerland.Roche Innovation Center Zurich, Schlieren, Switzerland.Medical Oncology, University Hospital Basel, Basel, Switzerland.Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.Medical Oncology, University Hospital Basel, Basel, Switzerland alfred.zippelius@usb.ch.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32616554

Citation

Trüb, Marta, et al. "Fibroblast Activation protein-targeted-4-1BB Ligand Agonist Amplifies Effector Functions of Intratumoral T Cells in Human Cancer." Journal for Immunotherapy of Cancer, vol. 8, no. 2, 2020.
Trüb M, Uhlenbrock F, Claus C, et al. Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. J Immunother Cancer. 2020;8(2).
Trüb, M., Uhlenbrock, F., Claus, C., Herzig, P., Thelen, M., Karanikas, V., Bacac, M., Amann, M., Albrecht, R., Ferrara-Koller, C., Thommen, D., Rothschield, S., Savic Prince, S., Mertz, K. D., Cathomas, G., Rosenberg, R., Heinzelmann-Schwarz, V., Wiese, M., Lardinois, D., ... Zippelius, A. (2020). Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. Journal for Immunotherapy of Cancer, 8(2). https://doi.org/10.1136/jitc-2019-000238
Trüb M, et al. Fibroblast Activation protein-targeted-4-1BB Ligand Agonist Amplifies Effector Functions of Intratumoral T Cells in Human Cancer. J Immunother Cancer. 2020;8(2) PubMed PMID: 32616554.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer. AU - Trüb,Marta, AU - Uhlenbrock,Franziska, AU - Claus,Christina, AU - Herzig,Petra, AU - Thelen,Martin, AU - Karanikas,Vaios, AU - Bacac,Marina, AU - Amann,Maria, AU - Albrecht,Rosemarie, AU - Ferrara-Koller,Claudia, AU - Thommen,Daniela, AU - Rothschield,Sacha, AU - Savic Prince,Spasenija, AU - Mertz,Kirsten D, AU - Cathomas,Gieri, AU - Rosenberg,Robert, AU - Heinzelmann-Schwarz,Viola, AU - Wiese,Mark, AU - Lardinois,Didier, AU - Umana,Pablo, AU - Klein,Christian, AU - Laubli,Heinz, AU - Kashyap,Abhishek S, AU - Zippelius,Alfred, PY - 2020/02/14/accepted PY - 2020/7/4/entrez PY - 2020/7/4/pubmed PY - 2020/7/4/medline KW - immunology KW - oncology KW - tumors JF - Journal for immunotherapy of cancer JO - J Immunother Cancer VL - 8 IS - 2 N2 - 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. SN - 2051-1426 UR - https://www.unboundmedicine.com/medline/citation/32616554/Fibroblast_activation_protein-targeted-4-1BB_ligand_agonist_amplifies_effector_functions_of_intratumoral_T_cells_in_human_cancer L2 - https://jitc.bmj.com/cgi/pmidlookup?view=long&pmid=32616554 DB - PRIME DP - Unbound Medicine ER -
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