RT Journal Article
SR Electronic
T1 Fibroblast activation protein-targeted-4-1BB ligand agonist amplifies effector functions of intratumoral T cells in human cancer
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000238
DO 10.1136/jitc-2019-000238
VO 8
IS 2
A1 Marta Trüb
A1 Franziska Uhlenbrock
A1 Christina Claus
A1 Petra Herzig
A1 Martin Thelen
A1 Vaios Karanikas
A1 Marina Bacac
A1 Maria Amann
A1 Rosemarie Albrecht
A1 Claudia Ferrara-Koller
A1 Daniela Thommen
A1 Sacha Rothschield
A1 Spasenija Savic Prince
A1 Kirsten D Mertz
A1 Gieri Cathomas
A1 Robert Rosenberg
A1 Viola Heinzelmann-Schwarz
A1 Mark Wiese
A1 Didier Lardinois
A1 Pablo Umana
A1 Christian Klein
A1 Heinz Laubli
A1 Abhishek S Kashyap
A1 Alfred Zippelius
YR 2020
UL http://jitc.bmj.com/content/8/2/e000238.abstract
AB 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.