Abstract
GAPDH is emerging as a key player in T cell development and function. To investigate the role of GAPDH in T cells, we generated a transgenic mouse model overexpressing GAPDH in the T cell lineage. Aged mice developed a peripheral Tfh-like lymphoma that recapitulated key molecular, pathological, and immunophenotypic features of human angioimmunoblastic T cell lymphoma (AITL). GAPDH induced non-canonical NF-κB pathway activation in mouse T cells, which was strongly activated in human AITL. We developed a NIK inhibitor to reveal that targeting the NF-κB pathway prolonged AITL-bearing mouse survival alone and in combination with anti-PD-1. These findings suggest the therapeutic potential of targeting NF-κB signaling in AITL and provide a model for future AITL therapeutic investigations.
Keywords:
NF-κB pathway; NF-κB-inducing kinase; PD1; T follicular helper cells; angioimmunoblastic T cell lymphoma; anti-PD1 immunotherapy; germinal center B cells; glyceraldehyde-3-phosphate-dehydrogenase; glycolytic enzyme; preclinical mouse model for AITL.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Animals
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Cell Line, Tumor
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Cell Lineage / immunology
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Datasets as Topic
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Disease Models, Animal
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Female
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Gene Knockdown Techniques
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / genetics
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / metabolism*
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HEK293 Cells
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Humans
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Immunoblastic Lymphadenopathy / genetics
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Immunoblastic Lymphadenopathy / pathology*
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Lymphoma, T-Cell / drug therapy
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / immunology
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Lymphoma, T-Cell / pathology*
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Male
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Mice, Transgenic
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Middle Aged
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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NF-kappaB-Inducing Kinase
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Protein Kinase Inhibitors / administration & dosage
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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NF-kappa B
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Protein Kinase Inhibitors
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GAPDH protein, human
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Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
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Protein Serine-Threonine Kinases