Renner, Kathrin and Bruss, Christina and Schnell, Annette and Koehl, Gudrun and Becker, Holger M. and Fante, Matthias and Menevse, Ayse-Nur and Kauer, Nathalie and Blazquez, Raquel and Hacker, Lisa and Decking, Sonja-Maria and Bohn, Toszka and Faerber, Stephanie and Evert, Katja and Aigle, Lisa and Amslinger, Sabine and Landa, Maria and Krijgsman, Oscar and Rozeman, Elisa A. and Brummer, Christina and Siska, Peter J. and Singer, Katrin and Pektor, Stefanie and Miederer, Matthias and Peter, Katrin and Gottfried, Eva and Herr, Wolfgang and Marchiq, Ibtisam and Pouyssegur, Jacques and Roush, William R. and Ong, SuFey and Warren, Sarah and Pukrop, Tobias and Beckhove, Philipp and Lang, Sven A. and Bopp, Tobias and Blank, Christian U. and Cleveland, John L. and Oefner, Peter J. and Dettmer, Katja and Selby, Mark and Kreutz, Marina (2019) Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy. CELL REPORTS, 29 (1). 135-+. ISSN 2211-1247,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR MICROENVIRONMENT; CYTOKINE PRODUCTION; LACTATE TRANSPORT; LACTIC-ACID; CANCER; MCT1; GLUCOSE; MACROPHAGES; METABOLISM; RESISTANCE; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Pathologie Chemistry and Pharmacy > Institut für Organische Chemie Chemistry and Pharmacy > Institut für Organische Chemie > Arbeitskreis Dr. Sabine Amslinger |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2020 11:25 |
| Last Modified: | 31 Mar 2020 11:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26156 |
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