Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization.
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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.
Enzyme-Linked Immunosorbent Assay
Polymerase Chain Reaction
Published Version (Please cite this version)10.1016/j.immuni.2017.12.004
Publication InfoZhao, 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.
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Medical Instructor in the Department of Medicine
I am an instructor of Medical Oncology who primarily treats patients with gastrointestinal malignancies. My laboratory and translational research is focused on tumor immune evasion and immunotherapy, with a specific interest in dendritic cell tolerance.
Associate Professor of Medicine
My lab is interested in elucidating the molecular and cellular mechanisms involved in tumor-mediated immune suppression and cancer immunotherapy resistance. Our overriding hypothesis is that tumor cells and/or their associated stromal elements elicit soluble factors that tolerize local dendritic cell populations and/or recruit other immunosuppressive cell populations to the tumor bed; thereby, interfering with the generation of an effective anti-tumor immune response. This work has both basic an
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.
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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