T cell stemness and dysfunction in tumors are triggered by a common mechanism

Abstract

A paradox of tumor immunology is that tumor-infiltrating lymphocytes are dysfunctional in situ, yet are capable of stem cell–like behavior including self-renewal, expansion, and multipotency, resulting in the eradication of large metastatic tumors. We find that the overabundance of potassium in the tumor microenvironment underlies this dichotomy, triggering suppression of T cell effector function while preserving stemness. High levels of extracellular potassium constrain T cell effector programs by limiting nutrient uptake, thereby inducing autophagy and reduction of histone acetylation at effector and exhaustion loci, which in turn produces CD8+ T cells with improved in vivo persistence, multipotency, and tumor clearance. This mechanistic knowledge advances our understanding of T cell dysfunction and may lead to novel approaches that enable the development of enhanced T cell strategies for cancer immunotherapy.

Histone acetylome-wide association study of tuberculosis

“…Autophagy is induced upon dephosphorylation of mTOR, which inhibits mTOR's activity 35 Similar suppression of Akt-mTOR signaling by increased [K + ]i has been described in T lymphocytes 36 . Overall, our results indicate that Kir4.2 is a conduit in the cell membrane for K + to enter monocytes, and its upregulation is a protective host response to Mtb infection.…”

The Role of Potassium Channels in the Pathogenesis of Gastrointestinal Cancers and Therapeutic Potential

“…Genes with a high SHAP score (>0.1) are extremely influential in the classification and therefore most associated with the query gene. The highest ranked WNT genes that correlate with KCNQ1 expression are transcription factors (TCF7, TLE3, RNF43) ( Figure 5 B ), interestingly TCF7 has been shown to be responsive to potassium in a tumor setting in immune cell populations (Vodnala et al, 2019). KCNQ3 classifications were mostly driven by membrane bound members of the WNT pathway and ligands (FZDs and WNTs).…”

Caloric restriction promotes the stemness and antitumor activity of T lymphocytes

“…In their recent work, Nick Restifo's team from the National Cancer Institute provides an integrated description of the metabolic, epigenetic, and biochemical events that lead to the formation of CD27 + CD62L + Tcf7 + TILs in the tumor bed. 6 In line with the notion that the tumor microenvironment (TME) shapes the phenotypic coevolution of tumor and immune cells, a prior report from the same group identified the ionic unbalance in TME as a leading cause of TIL dysfunction. 7 Excessive necrosis within neoplastic lesions significantly increases the extracellular concentration of potassium [K + ] e .…”