Publication Date:
2019
Description:
〈p〉Publication date: 1 October 2019〈/p〉
〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 29, Issue 1〈/p〉
〈p〉Author(s): Kathrin Renner, Christina Bruss, Annette Schnell, Gudrun Koehl, Holger M. Becker, Matthias Fante, Ayse-Nur Menevse, Nathalie Kauer, Raquel Blazquez, Lisa Hacker, Sonja-Maria Decking, Toszka Bohn, Stephanie Faerber, Katja Evert, Lisa Aigle, Sabine Amslinger, Maria Landa, Oscar Krijgsman, Elisa A. Rozeman, Christina Brummer〈/p〉
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〈h6〉Summary〈/h6〉
〈p〉Tumor-derived lactic acid inhibits T and natural killer (NK) cell function and, thereby, tumor immunosurveillance. Here, we report that melanoma patients with high expression of glycolysis-related genes show a worse progression free survival upon anti-PD1 treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers lactate secretion of tumor cells and improves anti-PD1-induced T cell killing 〈em〉in vitro〈/em〉. Surprisingly, diclofenac, but not other NSAIDs, turns out to be a potent inhibitor of the lactate transporters monocarboxylate transporter 1 and 4 and diminishes lactate efflux. Notably, T cell activation, viability, and effector functions are preserved under diclofenac treatment and in a low glucose environment 〈em〉in vitro〈/em〉. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy 〈em〉in vivo〈/em〉. Moreover, genetic suppression of glycolysis in tumor cells strongly improves checkpoint therapy. These findings support the rationale for targeting glycolysis in patients with high glycolytic tumors together with checkpoint inhibitors in clinical trials.〈/p〉
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〈h5〉Graphical Abstract〈/h5〉
〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719311234-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉
Electronic ISSN:
2211-1247
Topics:
Biology
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