Abstract 6163: Targeting glucose metabolism through inhibition of pyruvate dehydrogenase kinase to improve response to immune-checkpoint inhibition in melanoma
Authors: Tiersma Jiske F. , Evers Bernardus , Bakker Barbara M. , de Jong Steven , Jalving Mathilde 
Published: June 2022

Abstract
Immune-checkpoint inhibitors have improved survival of patients with advanced melanoma, however, 40-50% of patients do not benefit sufficiently. Melanoma tumor lesions have high glucose uptake due to metabolic reprogramming, which supports tumor cell growth and is partially mediated through elevated expression of mitochondrial pyruvate dehydrogenase kinases (PDK1-4). Resultant decreased glucose levels and low pH in the tumor microenvironment are detrimental to antitumor immune cell function. Here, we aimed to reverse metabolic reprogramming in melanoma through PDK inhibition, thereby inhibiting tumor cell growth while maintaining or potentially enhancing antitumor immunity. We used a panel of four melanoma cell lines with genetic backgrounds similar to those most frequently found in patients, namely the BRAF-mutant A375 and S-MEL-28 cell lines, the NRAS-mutant SK-MEL-2 cell line and the BRAF/NRAS wild-type MeWo cell line. These were then treated with PDK inhibitor dichloroacetate (DCA) to determine effects on viability and metabolic phenotype. Furthermore, we investigated whether DCA synergized with treatment with the glutaminase inhibitor CB-839. Finally, we determined the effect of DCA on viability, interferon-γ (IFN-γ) secretion and antitumor activity of CD8+ T cells. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA led to an up to 6-fold increase in oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio in all cell lines. SK-MEL-28 cells were not sensitive to CB-839, while the IC50 values in the other cell lines ranged from 7.9 nM in MeWo to 139.2 nM in SK-MEL-2 cells. DCA synergized with CB-839 in 2D and 3D culture, ranging from 2-fold sensitization compared to either drug alone in MeWo up to 5-fold sensitization in SK-MEL-2. In activated CD8+ T cells, viability was not affected by DCA treatment of up to 21 mM, whereas proliferation was only mildly inhibited. These cells also showed a 2.5-fold increase in OCR:ECAR ratio after DCA treatment. Interestingly, IFN-γ secretion by CD8+ T cells was increased 2.8-fold after DCA treatment and tumor cell killing by CD8+ T cells in a coculture with A375 cells was not impaired by DCA or CB-839 treatment. We conclude that DCA can indeed reprogram cellular metabolism in melanoma and synergizes with other metabolically targeted drugs in antitumor activity, while keeping the antitumor reactivity of CD8+ T cells intact. Supported by the Dutch Cancer Foundation (10913/2017-1).
Citation Format: Jiske F. Tiersma, Bernardus Evers, Barbara M. Bakker, Steven de Jong, Mathilde Jalving. Targeting glucose metabolism through inhibition of pyruvate dehydrogenase kinase to improve response to immune-checkpoint inhibition in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6163.