Journal Article

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

Finkel, Toren, Kruhlak, Michael J., Restifo, Nicholas P., Yamamoto, Tori N., Klebanoff, Christopher A., Eil, Robert, Sukumar, Madhusudhanan, Kishton, Rigel J., Shin, MinHwa, Patel, Shashank J., Palmer, Douglas C., Yu, Zhiya, Huang, Jing, Vodnala, Suman Kumar, Ha, Ngoc-Han, Locasale, Jason W., Liu, Xiaojing, Roychoudhuri, Rahul, Lee, Ping-Hsien

2019

Overview

T lymphocytes are powerful immune cells that can destroy tumors, but cancers have developed tricks to evade killing. Vodnala et al. found that potassium ions in the tumor microenvironment serve a dual role of influencing T cell effector function and stemness (see the Perspective by Baixauli Celda et al. ). Increased potassium impairs T cell metabolism and nutrient uptake, resulting in a starvation state known as autophagy. The increased potassium can also preserve T cells in a stem-like state where they retain the capacity to divide. These seemingly divergent processes are linked to the cellular distribution of acetyl–coenzyme A, which, when manipulated, can restore the ability of human T cells to eliminate tumors in mice. Science , this issue p. eaau0135 ; see also p. 1395 Potassium in the tumor microenvironment metabolically reprograms tumor-infiltrating immunological T cells. 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.

• Publisher: American Association for the Advancement of Science,The American Association for the Advancement of Science
• Subject: Acetyl Coenzyme A - metabolism / Acetylation / Animals / Anticancer properties / Antigens / Autophagy / Autophagy - immunology / Caloric Restriction / Cancer / Cancer immunotherapy / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell activation / Cell Differentiation - genetics / Cell self-renewal / Coenzyme A / Cofactors / Constraining / Depletion / Deprivation / Destruction / Dietary restrictions / DNA methylation / Electrochemistry / Enhancers / Epigenesis, Genetic / Epigenetics / Exhaustion / Gene therapy / Glycolysis / Histones - metabolism / Human performance / Humans / Immune checkpoint / Immune clearance / Immune system / Immune Tolerance / Immunology / Immunotherapy / Individualized Instruction / Intermediates / Intracellular / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Metabolism / Metastases / Metastasis / Methionine / Mice / Mice, Inbred C57BL / Mimicry / Necrosis / Neoplasms - immunology / Nutrient uptake / Nutrients / Persistence / Phagocytosis / Pharmacology / Potassium / Potassium - metabolism / RESEARCH ARTICLE SUMMARY / Starvation / Stem cells / Stem Cells - immunology / Tumor Microenvironment / Tumors