A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy

Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in...

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Published in:The Journal of experimental medicine Vol. 217; no. 12
Main Authors: Oda, Shannon K, Anderson, Kristin G, Ravikumar, Pranali, Bonson, Patrick, Garcia, Nicolas M, Jenkins, Cody M, Zhuang, Summer, Daman, Andrew W, Chiu, Edison Y, Bates, Breanna M, Greenberg, Philip D
Format: Journal Article
Language:English
Published: United States 07.12.2020
Subjects:
Animals
Cell Death - drug effects
Cell Engineering
Cell Proliferation - drug effects
Cell Survival - drug effects
Cytokines - metabolism
Disease Models, Animal
fas Receptor - metabolism
Humans
Immunologic Factors - pharmacology
Immunotherapy, Adoptive
Leukemia - immunology
Leukemia - pathology
Leukemia - therapy
Mice, Inbred C57BL
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - pathology
Phenotype
Recombinant Fusion Proteins - pharmacology
Signal Transduction - drug effects
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism
ISSN:1540-9538, 1540-9538
Online Access:Get more information
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Summary:Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor-positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies.
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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20191166