Abstract
The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.
Highlights
T lymphocytes undergo a metabolic reprogramming upon TCR-stimulation, which sustains the biosynthetic requirements of clonal expansion and differentiation
Plenty of evidence points at K+ as an interesting target for immunotherapy, the dual roles of K+ in anti-tumour T cells, the discrepancies observed in murine and human settings, and the direct effect of K+ on cancer cells indicate that further investigations are required to unveil the best strategy to exploit
Many clinical trials have demonstrated therapeutic efficacy of T-cell based immunotherapy, which exploits the capacity of T cells to recognize and kill a specific target, including cancer cells [104]
Summary
T lymphocytes undergo a metabolic reprogramming upon TCR-stimulation, which sustains the biosynthetic requirements of clonal expansion and differentiation. Overexpression of KCa 3.1 decreases intracellular [K+ ]I and restores T-cell Akt-mTOR signalling and IFNγ secretion, resulting in improved tumour growth control and survival [15] These reports indicate that levels of [K+ ]I and K+. A more recent report by Vodnala et al (2019) showed that despite dampening T-cell effector functions, mTOR inactivation derived from high [K+ ]e is accompanied by a decreased nutrient uptake, which initiates a starvation response The authors define this state as ‘functional caloric restriction’, characterised by autophagy induction and acetyl-CoA-dependent epigenetic remodelling (Figure 1). Plenty of evidence points at K+ as an interesting target for immunotherapy, the dual roles of K+ in anti-tumour T cells, the discrepancies observed in murine and human settings, and the direct effect of K+ on cancer cells indicate that further investigations are required to unveil the best strategy to exploit
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