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

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

Journal for immunotherapy of cancer (2020-07-04)
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
ABSTRACT

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. 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. 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. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
RPMI-1640 Medium, With sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium - high glucose, With 4500 mg/L glucose, L-glutamine, sodium pyruvate, and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Histopaque®-1077, sterile-filtered, density: 1.077 g/mL
Sigma-Aldrich
Anti-FAP Mouse mAb (F11-24), liquid, clone F11-24, Calbiochem®
Sigma-Aldrich
Hyaluronidase from sheep testes, Type V, lyophilized powder, ≥1,500 units/mg solid
Sigma-Aldrich
Deoxyribonuclease I from bovine pancreas, Type IV, lyophilized powder, ≥2,000 Kunitz units/mg protein