30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)
Elevated potassium levels suppress T cell activation within tumors
Journal for ImmunoTherapy of Cancer volume 3, Article number: P403 (2015)
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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Eil, R.L., Roychoudhuri, R., Clever, D. et al. Elevated potassium levels suppress T cell activation within tumors. j. immunotherapy cancer 3 (Suppl 2), P403 (2015). https://doi.org/10.1186/2051-1426-3-S2-P403