title: Metabolic perturbation sensitizes human breast cancer to NK cell-mediated cytotoxicity by increasing the expression of MHC class I chain-related A/B.
abstract: Cleavage or shedding of the surface antigen, MHC class I chain-related (MIC) protein (A/B) has been known to be one of the mechanisms by which tumor cells escape host immune surveillance. Thus, any strategy to augment the surface expression of MICA/B could facilitate anticancer immune response. Here, we demonstrate that metabolic perturbation by the glycolytic inhibitor, 3-bromopyruvate (3-BrPA) augments the surface expression of MICA/B in human breast cancer cell lines, MDA-MB-231 and T47D. Data fromin vitrostudies show that a non-toxic, low-dose of 3-BrPA is sufficient to perturb energy metabolism, as evident by the activation of p-AMPK, p-AKT and p-PI3K. Further, 3-BrPA-treatment also elevated the levels of MICA/B in human breast cancer cell lines. Significantly, 3-BrPA-dependent increase in MICA/B levels also enhanced the sensitivity of cancer cells to natural killer (NK-92MI)-mediated cytotoxicity.In vivo, 3-BrPA-pretreated cells demonstrated greater sensitivity to NK-92MI therapy than their respective controls. The antitumor effect was confirmed by a reduction in tumor size and decreased tumor viability as observed by bioluminescence imaging. Histological examination and TUNEL staining demonstrated that NK-92MI administration promoted apoptosis in 3-BrPA-pretreated cells. Taken together, our data show that targeting energy metabolism could be a novel strategy to enhance the effectiveness of anticancer immunotherapeutics.
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences; Johns Hopkins University School of Medicine ; Baltimore, MD, USA.
authors.forename: Dexue
authors.initials: D
authors.lastname: Fu
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences; Johns Hopkins University School of Medicine ; Baltimore, MD, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Geschwind
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences; Johns Hopkins University School of Medicine ; Baltimore, MD, USA.
authors.forename: Swathi
authors.initials: S
authors.lastname: Karthikeyan
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences; Johns Hopkins University School of Medicine ; Baltimore, MD, USA.
authors.forename: Eliyahu
authors.initials: E
authors.lastname: Miller
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences; Johns Hopkins University School of Medicine ; Baltimore, MD, USA.
authors.forename: Rani
authors.initials: R
authors.lastname: Kunjithapatham
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences; Johns Hopkins University School of Medicine ; Baltimore, MD, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Sciences; Johns Hopkins University School of Medicine ; Baltimore, MD, USA.
authors.forename: Shanmugasundaram
authors.initials: S
authors.lastname: Ganapathy-Kanniappan
keywords: MICA; NK cells; breast cancer; energy metabolism; immunotherapy