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

Nature. 2016 Sep 22;537(7621):539-543. doi: 10.1038/nature19364. Epub 2016 Sep 14.

Abstract

Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K+]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated [K+]e is independent of changes in plasma membrane potential (Vm), it requires an increase in intracellular potassium ([K+]i). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv1.3 lowers [K+]i and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cations, Monovalent / metabolism*
  • Humans
  • Immune Tolerance / immunology
  • Immunotherapy / methods
  • Kv1.3 Potassium Channel / metabolism
  • Male
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Melanoma / therapy
  • Membrane Potentials
  • Mice
  • Necrosis
  • Potassium / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • Survival Analysis
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Escape / immunology*
  • Tumor Microenvironment / immunology*

Substances

  • Cations, Monovalent
  • Kv1.3 Potassium Channel
  • Receptors, Antigen, T-Cell
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Potassium