Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy

• Main Authors: 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, Peter J. Siska, Katrin Singer, Stefanie Pektor, Matthias Miederer, Katrin Peter, Eva Gottfried, Wolfgang Herr, Ibtisam Marchiq, Jacques Pouyssegur, William R. Roush, SuFey Ong, Sarah Warren, Tobias Pukrop, Philipp Beckhove, Sven A. Lang, Tobias Bopp, Christian U. Blank, John L. Cleveland, Peter J. Oefner, Katja Dettmer, Mark Selby, Marina Kreutz
• Format: Article
• Language: English
• Published: Elsevier 2019-10-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124719311234

Summary: 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 in vitro. 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 in vitro. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy in vivo. 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. : Renner et al. demonstrate a negative correlation between glycolytic activity in tumors and response to checkpoint therapy. Genetic blockade of glycolysis or pharmacological inhibition of the main lactate transporters MCT1 and MCT4 preserves T cell function, reverses tumor acidification, and augments response to checkpoint therapy. Keywords: checkpoint, glycolysis, monocarboxylate transporters, lactate, acidification, diclofenac, T cells, NK cells, interferon gamma, tumor