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

Robert Eil, Suman K. Vodnala, David Clever, Christopher A. Klebanoff, Madhusudhanan Sukumar, Jenny H. Pan, Douglas C. Palmer, Alena Gros, Tori N. Yamamoto, Shashank J. Patel, Geoffrey C. Guittard, Zhiya Yu, Valentina Carbonaro, Klaus Okkenhaug, David S. Schrump, W. Marston Linehan, Rahul Roychoudhuri, Nicholas P. Restifo

    Research output: Contribution to journalArticlepeer-review

    221 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)539-543
    Number of pages5
    JournalNature
    Volume537
    Issue number7621
    DOIs
    StatePublished - Sep 14 2016

    ASJC Scopus subject areas

    • General

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