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

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: Marta Trüb, Franziska Uhlenbrock, Christina Claus, Petra Herzig, Martin Thelen, Vaios Karanikas, Marina Bacac, Maria Amann, Rosemarie Albrecht, Claudia Ferrara-Koller, Daniela Thommen, Sacha Rothschield, Spasenija Savic Prince, Kirsten D Mertz, Gieri Cathomas, Robert Rosenberg, Viola Heinzelmann-Schwarz, Mark Wiese, Didier Lardinois, Pablo Umana, Christian Klein, Heinz Laubli, Abhishek S Kashyap, Alfred Zippelius
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 2 (07 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32616554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 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.

Chemical References

• 4-1BB Ligand
• Receptors, Antigen, T-Cell

Topics

• 4-1BB Ligand (metabolism)
• Aged
• Fibroblasts (immunology)
• Humans
• Immunotherapy (methods)
• Neoplasms (genetics, pathology)
• Receptors, Antigen, T-Cell (metabolism)
• Transfection