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

Tumours progress despite being infiltrated by tumour-specific effector T cells1. Tumours contain areas of cellular necrosis, which is associated with poor survival in a variety of cancers2. Here, we show that necrosis releases an intracellular ion, potassium, into the extracellular fluid of mouse an...

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Detalles Bibliográficos
Autores principales: Eil, Robert, Vodnala, Suman K, Clever, David, Klebanoff, Christopher A, Sukumar, Madhusudhanan, Pan, Jenny H, Palmer, Douglas C, Gros, Alena, Yamamoto, Tori N, Patel, Shashank J, Guittard, Geoffrey C, Yu, Zhiya, Carbonaro, Valentina, Okkenhaug, Klaus, Schrump, David S, Linehan, W Marston, Roychoudhuri, Rahul, Restifo, Nicholas P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204372/
https://www.ncbi.nlm.nih.gov/pubmed/27626381
http://dx.doi.org/10.1038/nature19364
Descripción
Sumario:Tumours progress despite being infiltrated by tumour-specific effector T cells1. Tumours contain areas of cellular necrosis, which is associated with poor survival in a variety of cancers2. 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 PP2A3,4. While the suppressive effect mediated by elevated [K(+)]e is independent of changes in plasma membrane potential (V(m)), it does require an increase in intracellular potassium ([K(+)]i). Concordantly, ionic reprogramming of tumour-specific T cells through overexpression of the potassium channel K(v)1.3 lowers [K(+)]i and improves effector functions in vitro and in vivo. Consequently, K(v)1.3 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.