Journal
CANCER RESEARCH
Volume 74, Issue 21, Pages 6036-6047Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-1084
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Funding
- NIH [R21CA137725, R01CA138930, R01AR057643, R01CA104947, P20GM10354202, P01CA154778]
- [P30 CA138313]
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Ex vivo-expanded CD8(+) T cells used for adoptive immunotherapy generally acquire an effector memory-like phenotype (T-EM cells). With regard to therapeutic applications, two undesired features of this phenotype in vivo are limited persistence and reduced antitumor efficacy, relative to CD8(+) T cells with a central memory-like phenotype (T-CM cells). Furthermore, there is incomplete knowledge about all the differences between T-EM and T-CM cells that may influence tumor treatment outcomes. Given that T-CM cells survive relatively longer in oxidative tumor microenvironments, we investigated the hypothesis that T-CM cells possess relatively greater antioxidative capacity than T-EM cells. Here, we report that T-CM cells exhibit a relative increase compared with T-EM cells in the expression of cell surface thiols, a key target of cellular redox controls, along with other antioxidant molecules. Increased expression of redox regulators in T-CM cells inversely correlated with the generation of reactive oxygen and nitrogen species, proliferative capacity, and glycolytic enzyme levels. Notably, T-cell receptor-transduced T cells pretreated with thiol donors, such as N-acetyl cysteine or rapamycin, upregulated thiol levels and antioxidant genes. A comparison of antitumor CD8(+) T-cell populations on the basis of surface thiol expression showed that thiol-high cells persisted longer in vivo and exerted superior tumor control. Our results suggest that higher levels of reduced cell surface thiols are a key characteristic of T cells that can control tumor growth and that profiling this biomarker may have benefits to adoptive T-cell immunotherapy protocols. (C)2014 AACR.
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