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Series GSE84996 Query DataSets for GSE84996
Status Public on Aug 13, 2016
Title Ionic immune suppression within the tumour microenvironment limits T cell effector function
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design 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.
Contributor(s) Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP
Citation(s) 27626381, 38063845
Submission date Jul 29, 2016
Last update date Jan 16, 2024
Contact name Suman Kumar Vodnala
Phone 2408583809
Organization name NCI
Department Surgery Branch
Lab Nicholas Restifo Lab
Street address 10 Center Drive
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
Platforms (1)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (12)
GSM2255693 Veh_Stim_Repl_0
GSM2255694 Veh_Stim_Repl_1
GSM2255695 Veh_Stim_Repl_2
BioProject PRJNA335843
SRA SRP080338

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE84996_Eil_RNA-Seq_acutepotassium_FPKMvalues.txt.gz 1.1 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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