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Tumor Metabolism and the Microenvironment | EK14


Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma


Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

Description

Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma Tiersma JF1, Evers B2, Bakker BM2, de Jong S1, Jalving M1 1. Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 2. Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signaling, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 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 metabolic inhibitors. We treated a panel of melanoma cell lines with genetic backgrounds similar to those most frequently found in patients 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. DCA decreased expression of the phosphorylated (inactive) form of PDH (pPDH). DCA led to an up to threefold increase in the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio. Growth inhibition of DCA synergized with other metabolic inhibitors CB-839 (glutaminase inhibitor) and metformin. Synergy scores were over 20, indicating strong synergy, for DCA with CB-839 or DCA with metformin. 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 DCA reverses metabolic programming in melanoma cells. DCA toxicity was enhanced by other metabolic inhibitors, showing that DCA treatment also leads to dependency on other metabolic pathways. DCA treatment was non-toxic to immune cells and even enhanced interferon-γ response. Therefore, DCA may be a valuable tool to enhance treatment response in melanoma patients.

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