Ionic immune suppression within the tumour microenvironment limits T cell effector function

摘要

Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which is associated with poor survival in a variety of cancers. Here, we show that necrosis releases an intracellular ion, potassium, into the extracellular fluid of mouse and human tumours causing profound suppression of T cell effector function. We find that elevations in the extracellular potassium concentration [K⁺]e act to impair T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes, this potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A^,. While the suppressive effect mediated by elevated [K⁺]e is independent of changes in plasma membrane potential (Vm), it does require an increase in intracellular potassium ([K⁺]i). Concordantly, ionic reprogramming of tumour-specific T cells through overexpression of the potassium channel Kv1.3 lowers [K⁺]i and improves effector functions in vitro and in vivo. Consequently, Kv1.3 T cell overexpression enhances tumour clearance and survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint blocking T cell function within tumours and identify new strategies for cancer immunotherapy.