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

Area of Science:

• Immunology
• Cancer Biology
• Cell Physiology

Background:

• Tumour progression occurs despite T cell infiltration.
• Cellular necrosis in tumours correlates with poor patient survival.
• Necrosis releases intracellular components, potentially affecting the tumour microenvironment.

Purpose of the Study:

• To investigate the impact of necrosis-induced extracellular potassium on T cell function.
• To elucidate the molecular mechanisms underlying potassium-mediated T cell suppression.
• To explore therapeutic strategies targeting potassium levels for cancer immunotherapy.

Main Methods:

• Analysis of extracellular potassium concentration ([K+]e) in mouse and human tumours.
• Assessment of T cell receptor (TCR)-driven Akt-mTOR phosphorylation.
• Functional assays of T cell effector programmes in vitro and in vivo.
• Genetic manipulation of T cells to overexpress the potassium channel K_v1.3.

Main Results:

• Elevated extracellular potassium ([K+]e) from necrosis suppresses T cell effector function.
• High [K+]e impairs Akt-mTOR signalling via the phosphatase PP2A.
• Increased intracellular potassium ([K+]i) is required for suppression, independent of plasma membrane potential (Vm).
• Overexpression of K_v1.3 enhances T cell function and tumour clearance in melanoma models.

Conclusions:

• Necrosis-induced hyperkalemia creates an 'ionic checkpoint' inhibiting anti-tumour T cell responses.
• Targeting potassium efflux represents a novel strategy for enhancing cancer immunotherapy.
• Modulating T cell potassium levels can improve tumour eradication and patient survival.