Promoting Thiol Expression Increases the Durability of Antitumor T-cell Functions

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.