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E-GEOD-84996 - Ionic immune suppression within the tumour microenvironment limits T cell effector function
Released on 13 August 2016, last updated on 21 August 2016
Tumours progress despite being infiltrated by effector T cells. Tumour necrosis is associated with poor survival in a variety of cancers. Here, we report that that necrosis causes release of an intracellular ion, potassium, into the extracellular fluid of human and mouse tumours. Surprisingly, elevated extracellular potassium ([K+]e) was sufficient to profoundly suppress mouse and human T cell anti-tumour function. Elevations in [K+]e acted to acutely impair T cell receptor (TCR) dependent Akt-mTOR phosphorylation and effector function. Potassium mediated suppression of Akt-mTOR signalling and T cell effector function required intact activity of PP2A, a serine/threonine phosphatase. The suppressive effect mediated by elevated [K+]e required a T cell-intrinsic increase in intracellular potassium ([K+]i) and was independent of changes in plasma membrane potential (Vm). Finally, ionic reprogramming of tumour-specific T cells via over-expression of the voltage-gated potassium channel Kv1.3 lowered [K+]i and improved effector functions in vitro and in vivo, with this gain of function being dependent on intact channel function. Consequently, Kv1.3 T cell expression enhanced tumour clearance and the survival of melanoma-bearing mice. These results uncover a previously undescribed ionic checkpoint against T cell function within tumours and identify new strategies for cancer immunotherapy. RNA expression was measured by RNA-Seq on day 5 of cultures, maintained in individual biologial triplicates which were stimulated with immobilized anti-CD3/28 antibodies or kept in complete media (no stim) - with equivalent conditions treated with isotonic media containing elevated potassium.
RNA-seq of coding RNA
Suman Kumar Vodnala <firstname.lastname@example.org>, Alena Gros, Christopher A Klebanoff, David Clever, David S Schrump, Douglas C Palmer, Geoff C Guittard, Jenny H Pan, Klaus Okkenhaug, Madhusudhanan Sukumar, Nicholas P Restifo, Rahul Roychoudhuri, Robert Eil, Shashank J Patel, Suman K Vodnala, Tori N Yamamoto, Valentina Carbonaro, W M Linehan, Zhiya Yu