Since melanoma patients with high tumor glycolytic activity have shorter PFS after anti-PD-1 treatment, Renner and Bruss et al. investigated the impact of lactate levels on tumor responses to checkpoint inhibition (CPI). In tumor cell lines, the NSAID diclofenac potently inhibited lactate transporters MCT1 and 4 in a COX-independent manner, preserved human CD4+ and CD8+ T cell function and IFNγ expression, and induced a metabolic shift from glycolytic to oxidative TCA pathways. Diclofenac and CPI decreased tumor growth in B16 and 4T1 mouse models (significantly in the latter) compared to CPI alone, providing rationale for clinically testing the combination.
Contributed by Katherine Turner
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.
Author Info: (1) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany; Regensburg Center for Interventional Immunology, Regensburg, Germany. Electronic addre
Author Info: (1) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany; Regensburg Center for Interventional Immunology, Regensburg, Germany. Electronic address: kathrin.renner-sattler@ukr.de. (2) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (3) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (4) Department of Surgery, University Hospital Regensburg, Regensburg, Germany. (5) Division of General Zoology, University of Kaiserslautern, Kaiserslautern, Germany. (6) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (7) Regensburg Center for Interventional Immunology, Regensburg, Germany. (8) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (9) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (10) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (11) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (12) Institute for Immunology, University Medical Center Johannes Gutenberg University (UMC) Mainz, Mainz, Germany. (13) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (14) Institute of Pathology, University of Regensburg, Regensburg, Germany. (15) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (16) Institute of Organic Chemistry, University of Regensburg, Regensburg, Germany. (17) Institute of Organic Chemistry, University of Regensburg, Regensburg, Germany. (18) Department Medical Oncology and Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (19) Department Medical Oncology and Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (20) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (21) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (22) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (23) Department of Nuclear Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. (24) Department of Nuclear Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. (25) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (26) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (27) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (28) Institute of Research on Cancer and Aging (IRCAN), CNRS-INSERM-UNS UMR 7284, Nice, France. (29) Institute of Research on Cancer and Aging (IRCAN), CNRS-INSERM-UNS UMR 7284, Nice, France; Department of Medical Biology, Scientific Centre of Monaco (CSM), Monaco. (30) Department of Chemistry, The Scripps Research Institute, Scripps-Florida, Jupiter, FL, USA. (31) NanoString Technologies, Seattle, WA, USA. (32) NanoString Technologies, Seattle, WA, USA. (33) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. (34) Regensburg Center for Interventional Immunology, Regensburg, Germany. (35) Department of General and Visceral Surgery, Medical Center, Faculty of Medicine University of Freiburg, Freiburg, Germany. (36) Institute for Immunology, University Medical Center Johannes Gutenberg University (UMC) Mainz, Mainz, Germany; Research Center for Immunotherapy (FZI), UMC Mainz, Mainz, Germany; University Cancer Center Mainz, UMC Mainz, Mainz, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. (37) Department Medical Oncology and Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (38) Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (39) Institute of Functional Genomics, University of Regensburg, Regensburg, Germany. (40) Institute of Functional Genomics, University of Regensburg, Regensburg, Germany. (41) Bristol-Myers Squibb, Redwood City, CA, USA. (42) Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany; Regensburg Center for Interventional Immunology, Regensburg, Germany.
