Abstract PO-020: Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma

Abstract

Abstract Immune checkpoint inhibitors improve long term survival of advanced melanoma patients, however, 40-50% of patients do not benefit. Reprogrammed tumor metabolism may hinder immune cell function. We aimed to reverse metabolic reprogramming in melanoma cells by inhibiting pyruvate dehydrogenase (PDK), thereby reducing lactate secretion, while preserving or enhancing immune cell activity. In addition, we strived to elucidate metabolic vulnerabilities arising during PDK inhibitor treatment by co-treating cells with other metabolically targeted inhibitors. We treated a panel of melanoma cell lines with genetic backgrounds similar to those most frequently found in the clinic with PDK inhibitor dichloroacetate (DCA) to determine effects on viability, expression of metabolic proteins and oxygen consumption/lactate secretion. IC50 values for DCA were 14.9 ± 1.0 for A375, 13.3 ± 0.6 for MeWo, 20.0 ± 1.4 for SK-MEL-28 and 27.3 ± 1.7 mM for SK-MEL-2 cells. PDK inhibition decreased expression of the phosphorylated (inactive) form of PDH (pPDH) in melanoma cells. DCA treatment led to an up to threefold increase in the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio in melanoma cells. Growth inhibition of DCA synergized with other metabolic inhibitors CB-839 (glutaminase inhibitor) and metformin. The combination index (CI) was less than 0.5, indicating strong synergy, for DCA with CB-839 or DCA with metformin in several models. DCA at concentrations affecting OCR:ECAR ratio of melanoma cells (7 mM) had only minimal effects on proliferation of activated T cells and peripheral blood mononuclear cells (PBMCs). Interestingly, the interferon-γ level as a marker of cytotoxicity was increased by DCA in culture media of both T cells and PBMCs. We conclude that PDK inhibition through DCA reverses metabolic programming in melanoma cells. Also, DCA toxicity was enhanced by other metabolic inhibitors, showing that DCA treatment leads to dependency on other metabolic pathways. DCA treatment was non-toxic to immune cells and even enhanced cytotoxicity. Therefore, DCA may be a valuable tool in improving response to immunotherapy in melanoma patients. Citation Format: Jiske F. Tiersma, Bernard Evers, Barbara M. Bakker, Steven de Jong, Mathilde Jalving. Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-020.