Acidic Tumor Microenvironment Facilitate Immunosuppressive MDSCs Through ASICs

Immune suppression state could be induced by Myeloid-derived suppressor cells(MDSCs),a key group of cells,under tumor acidic microenvironment and it often leads to the failure of tumor immunotherapy.Acid-sensing ion channels(ASICs)is known as the H-gated cation channels,it can perceive H~+gradient of cell through the channel.We assumed that ASICs acted as sensors for extracellular acidosis and regulate the responses of MDSCs to acidosis in tumor microenvironment.We preliminary explored the expression of ASICs in mouse MDSCs and roles of ASICs in the effect and mechanism of acidosis on MDSCs function.The work above may provide a new pharmacological target for tumor immunotherapy.1.The regulation of MDSCs function in tumor acidification microenvironmentWhen the pH is to 5.5,it can promote MDSCs to secrete the expression of ROS,COX-2,TNF-?,ARG-1.Pretreatment with amiloride can significantly inhibit the cytokine secretion of MDSCs under acid environment;ASIC 1 inhibitor,PcTx1,can inhibit the expression of TNF-α;ASIC 3 inhibitor,APET×2,significantly reduced COX-2 secretion,and both were able to reduce the production of ROS and ARG-1.Further studies have found that APET×2 can reverse the inhibitory effect of MDSCs on the proliferation of T cells in advance,so that the proliferation of T cells significantly increased to normal levels.These results suggest that ASIC1,3 plays an important role in the activation of MDSCs in acidic environment.2.The molecular mechanisms of the influence on MDSCs in tumor acidification microenvironment.2.1 The p38 phosphorylation level of MDSCs from tumor-bearing significantly increased than that of normal mice.When pretreated with amiloride,acidification induced p38 activation was markedly suppressed.Similarly,environmental acidification can stimulate MDSCs NF-κB pathway-p65 activation,and we found that PcTx1 can inhibit p-p65,pIκB,pIKK phosphorylation inhibition of NF kappa B pathway activation;APET×2 has no obvious effects on the signaling pathway.It may suggest that the acidification of tumor microenvironment can enhance MDSCs suppressive immune activity through NF-κB signaling pathway and is closely related with ASIC 1.2.2 Use the same methods,it was found that the pSTAT 1,pSTAT 6phosphorylation levels were closely related with ASIC1,ASIC3.It suggested that acidification conditions could stimulate the activation of transcription factor STAT1and STAT6 through ASIC 1 and ASIC 3,or respectively.Conclusion:(1)The acidification of tumor microenvironment can promote the expression of ROS,COX-2,TNF-α,ARG-1.PcTx1 can reduce the expression of TNF-αand APET×2 can reduce the expression of COX-2.Both of them can reduce the expression of ROS and ARG-1.PcTx1 and APET×2 can stimulate MDSCs activation and reverse MDSCs on T cells inhibition.(2)In acidification of tumor microenvironment,the activation of NF-κB was related with ASIC1.At the same time,it can stimulate ASIC1 and ASIC3 to activate STAT1 and STAT6 phosphorylation,and then play an important role of immunosuppression to mediate MDSCs activation.