Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy

• DOI: 10.1016/j.celrep.2019.08.068
• Publication Date: 2019-10-01T14:34:32Z
• 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
• Keywords: T-Lymphozyt; 0301 basic medicine; Diclofenac; Natürliche Killerzelle; QH301-705.5; ddc:540; T-Lymphocytes; Interferon (gamma-); 610 Medizin; 610; Glykolyse; Mice; Xenopus laevis; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Biology (General); Cell Proliferation; Fixpunkt (Datensicherung); ddc:610; Mice, Inbred BALB C; Tumor; Anti-Inflammatory Agents, Non-Steroidal; checkpoint; glycolysis; monocarboxylate transporters; lactate; acidification; diclofenac; T cells; NK cells; interferon gamma; tumor; 3. Good health; Mice, Inbred C57BL; Glucose; 540 Chemie; Lactate; Glycolysis

•Glycolytic index in melanoma negatively correlates with response to anti-PD1 therapy•Blocking lactate transport or knock out of glycolytic genes improves checkpoint therapy•Diclofenac blocks the transporters MCT1 and MCT4 a COX-independent manner•Inhibition glycolysis by MCT blockade does not impede T cell function SummaryTumor-derived lactic acid inhibits natural killer (NK) and, thereby, tumor immunosurveillance. Here, we report that patients high expression glycolysis-related show worse progression free survival upon treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers secretion cells anti-PD1-induced killing vitro. Surprisingly, diclofenac, but other NSAIDs, turns be potent inhibitor monocarboxylate transporter 1 4 diminishes efflux. Notably, activation, viability, effector functions are preserved under treatment low glucose environment Diclofenac, aspirin, delays growth efficacy therapy vivo. Moreover, genetic suppression strongly therapy. These findings support rationale for targeting tumors together inhibitors clinical trials. Tumor-derived