Intracellular K ⁺ limits T cell exhaustion and preserves antitumor function

The cancer-killing activity of T cells is often compromised within tumors, allowing disease progression. We previously found that intratumoral elevations in extracellular K ⁺ related to ongoing cell death constrained CD8 ⁺ T cell Akt-mTOR signaling and effector function (1,2). To alleviate K ⁺ mediated T cell suppression, we pursued genetic means to lower intracellular K ⁺ . Transcriptomic analysis of CD8 ⁺ T cells demonstrated the Na ⁺ /K ⁺ ATPase to be robustly and dynamically expressed. CRISPR-Cas9 mediated deletion of the catalytic alpha subunit of the Na ⁺ /K ⁺ ATPase lowered intracellular K ⁺ but produced tonic hyperactivity in multiple signal transduction cascades along with the acquisition of co-inhibitory receptors and terminal differentiation in mouse and human CD8 ⁺ T cells. Mechanistically, Na ⁺ /K ⁺ ATPase disruption led to ROS accumulation due to depletion of intracellular K ⁺ in T cells. Antioxidant treatment or high K ⁺ media prevented Atp1a1 deficient T cells from exhausted T (T _Ex ) cell formation. Consistent with transcriptional and proteomic data suggesting a T _Ex cell phenotype, T cells lacking Atp1a1 had compromised persistence and antitumor activity in a syngeneic model of orthotopic murine melanoma. Translational application of these findings will include efforts to lower intracellular K ⁺ while limiting ROS accumulation within tumor specific T cells.

High extracellular K ⁺ (↑[K ⁺ ] _e ) is found within tumors and suppresses T cell effector function. Collier et al. find that deletion of the Na ⁺ /K ⁺ ATPase in T cells lowers intracellular K ⁺ and promotes ROS accumulation, tonic signal transduction and T cell exhaustion owing to ROS accumulation. Engineering T cell ion transport is an important consideration for cancer immunotherapy.