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RESEARCH PRODUCT
LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells
Wolfgang Mueller-klieserEvelyn UllrichE. K. GeisslerAndreas VillungerAlmut BrandSigrid KarrerKathrin RennerKathrin RennerAndré StevenPeter J. OefnerStefan WalentaElisabeth KohlAnnette ThielChristian U. BlankGudrun E. KoehlJacques PouysségurSebastian HaferkampMaximilian SchmidMaximilian SchmidMarina KreutzMarina KreutzCarina MatosStefan Fichtner-feiglStefan Fichtner-feiglKatja DettmerPetra HoffmannPetra HoffmannUlrike SchleicherSebastian KlobuchBarbara SeligerKatrin SingerMichael KastenbergerChristian BogdanMatthias MackMatthias MackMark BerneburgK. PeterK. PeterStephan SchremlUwe RitterWolfgang HerrMarlene KolitzusAndreas MackensenChristina BrussRebecca KesselringGabriele Schoenhammersubject
Male0301 basic medicineCell SurvivalPhysiologyT-LymphocytesT cellApoptosisCell CountCD8-Positive T-LymphocytesBiologySodium LactateInterferon-gamma03 medical and health scienceschemistry.chemical_compoundInterleukin 21Downregulation and upregulationCell Line TumormedicineAnimalsHumansLactic AcidImmunologic SurveillanceMelanomaMolecular BiologyCell ProliferationL-Lactate DehydrogenaseNFATC Transcription FactorsNFATCell Biologymedicine.diseaseUp-RegulationLactic acidIsoenzymesKiller Cells NaturalMice Inbred C57BLPhenotype030104 developmental biologymedicine.anatomical_structurechemistryCell cultureImmunologyCancer researchInterleukin 12CytokinesLactate Dehydrogenase 5GlycolysisInfiltration (medical)description
Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldhalow) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2-/-γc-/- mice, lacking lymphocytes and NK cells, and in Ifng-/- mice, Ldhalow and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-10-16 | Cell Metabolism |