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Ionic Control of T-Cell Function

T-cell differentiation exists on a spectrum that defines their degree of naivety. It's been shown that differentiation dictates the cells anti-tumor protentional, cytokine production, capacity for proliferation (Restifo NP, et al. NatRev Cancer 2012). While naïve T-cells have the most protentional to differentiate and persist, they lack in ability to proficiently destroy tumor cells. Our most potent cytolytic cells, CD8+ T-Effector cells, can quickly become terminally exhausted in the harsh tumor microenvironment. Much has been elucidated in the mechanisms that tumors use to keep the immune system at bay and a precious few of these discoveries have yielded effective novel treatments.

While many factors in the tumor microenvironment work to suppress T-cell function, the effects of ions remained unexamined. In prior work, we've shown that cancer cell death releases potassium ions into the extracellular space at greater local concentrations than normal physiological levels. Futhermore, the elevated levels of potassium directly suppresses TCR activation and drives a metabolic reprogramming to maintain T-cell stemness. This novel finding begs more questions as to the mechanism and possible implications in treatment. At the Eil lab we seek to find translatable solutions for treatment of solid cancers.

We previously found that ↑[K+]e within the TME acts as an ionic checkpoint on T cell anti-tumor activity, inducing dysfunction. This work established extracellular potassium concentration as a novel means of tumor-induced immune evasion and manipulation of ion transport as a means to control T cell function (Eil R, et al. Nature 2016). Ensuing work focused on the downstream consequences upon T cell function and maturation following exposure to ↑[K+]e, and revealed that ↑[K+]e durably alters T cell metabolism and epigenetic programs that determine behavior (Vodnala SK* & Eil R* et al. Science 2019). Despite these observations, prior models defining K+ in T cells, cannot account for these observations.

Prior models ascribed K+ transport in T cells to be solely a facilitator of T cell receptor induced Ca2+ influx. However, our prior findings and ongoing work in the lab implicate K+ abundance and transport as central to T cell metabolism and homeostasis.  We continue to actively pursuing this line of research with both a depth (hypothesis directed interrogations) and breadth (in vivo CRISPR-Cas9 functional screens), along with the development of novel reporters and reagents to study K+ dynamics in T cells. Our ongoing work in this area suggests that intracellular K+ concentration acts as a central regulator of homeostasis and metabolism required for T cell antitumor function. We are actively leveraging these ongoing findings into novel and proprietary approaches to engineer T cell function.  

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Updated 01/16/2024 15:02 PST