期刊
THERANOSTICS
卷 10, 期 10, 页码 4481-4489出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.41646
关键词
TNF; AICD; mitochondria hyperpolarization; DNA damage
资金
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2014-52361-R, SAF 2017-83267-C2-1R]
- Cancer Research Institute (CRI)
- Asociacion Espanola Contra el Cancer (AECC) Foundation [GCB15152947MELE]
- Joint Translational Call for Proposals 2015 (JTC 2015) TRANSCAN-2 [TRS-2016-00000371]
- Fondo de Investigacion Sanitaria-Fondo Europeo de Desarrollo Regional (FEDER) [PI14/01686, PI13/00207, PI16/00668, PI19/01128]
- H2020 PROCROP project [635122]
- Marie Sklodowska-Curie fellowship [CINK 746985]
- la Caixa Banking Foundation [LCF/BQ/LR18/11640014]
Activation-induced cell death (AICD) is a complex immunoregulatory mechanism that causes the demise of a fraction of T-lymphocytes upon antigen-driven activation. In the present study we investigated the direct role of TNF in AICD of CD8 T lymphocytes. Methods: Human peripheral mononuclear cells were isolated from healthy donors and fresh tumor-infiltrating lymphocytes were obtained from cancer patients undergoing surgery. T cells were activated with anti-CD3/CD28 mAbs or with a pool of virus peptides, in combination with clinical-grade TNF blocking agents. Results: A portion of CD8 T cells undergoes apoptosis upon CD3/CD28 activation in a manner that is partially prevented by the clinically used anti-TNF agents infliximab and etanercept. TNF-mediated AICD was also observed upon activation of virus-specific CD8 T cells and tumor-infiltrating CD8 T lymphocytes. The mechanism of TNF-driven T cell death involves TNFR2 and production of mitochondrial oxygen free radicals which damage DNA. Conclusion: The use of TNF blocking agents reduces oxidative stress, hyperpolarization of mitochondria, and the generation of DNA damage in CD8 T celss undergoing activation. The fact that TNF mediates AICD in human tumor-reactive CD8 T cells suggests that the use of TNF-blocking agents can be exploited in immunotherapy strategies.
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