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

By R. Eil, S. Vodnala, D. Clever, C. Klebanoff, Madhusudhanan Sukumar, J. Pan, D. Palmer, A. Gros, Tori N. Yamamoto, Shashank J. Patel and 8 more. Nature, 2016

607 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/d1b891d387f3b4753058241d426357e9008d7ec5

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In Immunology

1. S. Grivennikov
2. C. June
3. F. Greten
4. Wendell A. Lim
5. M. Karin

In Oncology

1. C. June
2. S. Grivennikov
3. Wendell A. Lim
4. F. Greten
5. M. Karin

Citations in the corpus

• The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “1 (encoded by the KCNN4 gene) restores their antitumor activity (Eil et al., 2016).”
• Inflammation and Cancer: Triggers, Mechanisms and Consequences (2019, background): “, 2018) and similar processes can be enforced by regulatory T cells and by metabolic products of TME, such as hypoxia, glutamine or potassium ions (Clever et al., 2016; Eil et al., 2016; Johnson et al., 2018).”