Cellular metabolism has been shown to regulate differentiation and function of immune cells.Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor...Cellular metabolism has been shown to regulate differentiation and function of immune cells.Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments.NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials.However,the influences of tumor microenvironments on NKT cell functions remain unclear.In our studies,lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells,and more profound influence on IFNγ was observed.By adjusting the pH of culture medium we further showed that,dysfunction of NKT cells could simply be induced by low extracellular pH.Moreover,low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin(mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger(PLZF).Together,our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.展开更多
基金supported by the Major State Basic Research Development Program of China(2013CB944902)National Natural Science Foundation of China(31271430,31470859,91542203)Fundamental Research Funds for the Central Universities,and Users with Potential(2015HSC-UP018)
文摘Cellular metabolism has been shown to regulate differentiation and function of immune cells.Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments.NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials.However,the influences of tumor microenvironments on NKT cell functions remain unclear.In our studies,lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells,and more profound influence on IFNγ was observed.By adjusting the pH of culture medium we further showed that,dysfunction of NKT cells could simply be induced by low extracellular pH.Moreover,low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin(mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger(PLZF).Together,our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.
