Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization.
Abstract
Despite recent advances, many cancers remain refractory to available immunotherapeutic
strategies. Emerging evidence indicates that the tolerization of local dendritic cells
(DCs) within the tumor microenvironment promotes immune evasion. Here, we have described
a mechanism by which melanomas establish a site of immune privilege via a paracrine
Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway
that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the
carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased
the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while
suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced
IDO activity and the generation of regulatory T cells. We demonstrated that blockade
of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1
antibody immunotherapy, and suppressed disease progression in a transgenic melanoma
model. This work implicates a role for tumor-mediated metabolic reprogramming of local
DCs in immune evasion and immunotherapy resistance.
Type
Journal articleSubject
Dendritic CellsCell Line
Animals
Mice, Transgenic
Mice
Melanoma
Fatty Acids
PPAR gamma
Immunoblotting
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Polymerase Chain Reaction
Paracrine Communication
Signal Transduction
Female
Male
beta Catenin
Wnt-5a Protein
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https://hdl.handle.net/10161/17695Published Version (Please cite this version)
10.1016/j.immuni.2017.12.004Publication Info
Zhao, Fei; Xiao, Christine; Evans, Kathy S; Theivanthiran, Tbalamayooran; DeVito,
Nicholas; Holtzhausen, Alisha; ... Hanks, Brent A (2018). Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic
Cell Tolerization. Immunity, 48(1). pp. 147-160.e7. 10.1016/j.immuni.2017.12.004. Retrieved from https://hdl.handle.net/10161/17695.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Nicholas Christian DeVito
Assistant Professor of Medicine
I am an Assistant Professor of Medical Oncology who primarily treats patients with
colon cancer and gastroesophageal cancers. My laboratory and translational research
is focused on tumor immune evasion and immunotherapy, particularly in the setting
of metastasis. This work has led to a specific interest in tumor-mediated development
of dendritic cell tolerance and suppressive myeloid populations. The ultimate goal
of this research is to create biomarker-directed immunotherapies for advanced gast
Brent A. Hanks
Associate Professor of Medicine
We are interested in understanding the mechanisms that cancers have evolved to suppress
the generation of tumor antigen-specific immune responses and how this knowledge can
be exploited for the development of novel and more effective cancer immunotherapy
strategies. This work involves the utilization of both autochthonous transgenic tumor
model systems as well as clinical specimens to develop novel strategies to enhance
the efficacy of immunotherapies while also developing predictive biomarkers
Jason Locasale
Associate Professor of Pharmacology and Cancer Biology
Our research interests are in three interconnected areas: 1) Quantitative and computational
biology of metabolism. 2) The role of diet and pharmacological therapeutics in shaping
metabolic pathways in health and cancer. 3) The interaction of metabolism and epigenetics.
Each of these synergistic areas utilizes the metabolomics technologies we develop
along with our expertise in computational and molecular biology.
Smita K Nair
Professor in Surgery
I have 22 years of experience in the field of cancer vaccines and immunotherapy and
I am an accomplished T cell immunologist. Laboratory website:https://surgery.duke.edu/immunology-inflammation-immunotherapy-laboratory
Current projects in the Nair Laboratory:1] Dendritic cell vaccines using tumor-antigen
encoding RNA (mRNA, total tumor RNA, amplified tumor mRNA)<br
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