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

Abstract

<div>Abstract<p><i>Ex vivo</i>–expanded CD8<sup>+</sup> T cells used for adoptive immunotherapy generally acquire an effector memory-like phenotype (T<sub>EM</sub> cells). With regard to therapeutic applications, two undesired features of this phenotype <i>in vivo</i> are limited persistence and reduced antitumor efficacy, relative to CD8<sup>+</sup> T cells with a central memory-like phenotype (T<sub>CM</sub> cells). Furthermore, there is incomplete knowledge about all the differences between T<sub>EM</sub> and T<sub>CM</sub> cells that may influence tumor treatment outcomes. Given that T<sub>CM</sub> cells survive relatively longer in oxidative tumor microenvironments, we investigated the hypothesis that T<sub>CM</sub> cells possess relatively greater antioxidative capacity than T<sub>EM</sub> cells. Here, we report that T<sub>CM</sub> cells exhibit a relative increase compared with T<sub>EM</sub> 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<sub>CM</sub> 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<sup>+</sup> T-cell populations on the basis of surface thiol expression showed that thiol-high cells persisted longer <i>in vivo</i> 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. <i>Cancer Res; 74(21); 6036–47. ©2014 AACR</i>.</p></div>