Elevated potassium levels suppress T cell activation within tumors
KeywordsTreg Cell Okadaic Acid Adaptive Immune System Peptide Inhibitor Promote Tumor Growth
Tumors progress in immunocompetent hosts despite the ability of the adaptive immune system to recognize cancer cells. Ion gradients regulate T cell function but their role in intratumoral immune responses is unexplored. We found that the concentration of K+ was strikingly elevated within tumors while the concentration of the divalent cations Ca2+ and Mg2+ was similar to serum levels. High K+ levels significantly blunted cytokine production and suppression TCR stimulation induced gene transcription in CD8+ and CD4+ effector T cells. Moreover, polarization of CD8+ and CD4+ T cells in high K+ suppressed effector differentiation and promoted the formation of CD4+ Foxp3+ Treg cells. Surprisingly, this was not due to an attenuation of TCR induced Ca2+ flux, but rather to reduced activation of the serine/threonine Akt-mTOR pathway and could be partially reversed by overexpression of constitutively active Akt1. This coincided with the finding that okadaic acid, an inhibitor of the serine/threonine phosphatase PP2A, rendered effector cells resistant to the inhibitory effects of high K+ and restored cytokine function within tumors. Additionally, expression of a peptide inhibitor targeting the PP2A complex provided resistance to the inhibitory effect of elevated K+. These findings identify a novel mechanism of ionic regulation of TCR induced signals and immunosuppression within tumors whereby locally high extracellular concentrations of normally intracellular ions suppress immune function to promote tumor growth.
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