T cell stemness and dysfunction in tumors are triggered by a common mechanism
- Authors
- Vodnala, Suman Kumar; Eil, Robert; Kishton, Rigel J.; Sukumar, Madhusudhanan; Yamamoto, Tori N.; Ngoc-Han Ha; Lee, Ping-Hsien; Shin, MinHwa; Patel, Shashank J.; Yu, Zhiya; Palmer, Douglas C.; Kruhlak, Michael J.; Liu, Xiaojing; Locasale, Jason W.; Huang, Jing; Roychoudhuri, Rahul; Finkel, Toren; Klebanoff, Christopher A.; Restifo, Nicholas P.
- Issue Date
- 29-3월-2019
- Publisher
- AMER ASSOC ADVANCEMENT SCIENCE
- Citation
- SCIENCE, v.363, no.6434, pp.1417 - +
- Indexed
- SCIE
SCOPUS
- Journal Title
- SCIENCE
- Volume
- 363
- Number
- 6434
- Start Page
- 1417
- End Page
- +
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/66592
- DOI
- 10.1126/science.aau0135
- ISSN
- 0036-8075
- 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.
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