title: Promoting thiol expression increases the durability of antitumor T-cell functions.
abstract: Ex vivo-expanded CD8(+) T cells used for adoptive immunotherapy generally acquire an effector memory-like phenotype (TEM 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 (TCM cells). Furthermore, there is incomplete knowledge about all the differences between TEM and TCM cells that may influence tumor treatment outcomes. Given that TCM cells survive relatively longer in oxidative tumor microenvironments, we investigated the hypothesis that TCM cells possess relatively greater antioxidative capacity than TEM cells. Here, we report that TCM cells exhibit a relative increase compared with TEM 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 TCM 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.
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Pravin
authors.initials: P
authors.lastname: Kesarwani
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Al-Khami
authors.affiliation: Department of Surgery, Loyola University, Maywood, IL 60153.
authors.forename: Gina
authors.initials: G
authors.lastname: Scurti
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Thyagarajan
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Navtej
authors.initials: N
authors.lastname: Kaur
authors.affiliation: Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Shahid
authors.initials: S
authors.lastname: Husain
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Osama S
authors.initials: OS
authors.lastname: Naga
authors.affiliation: Department of Surgery, Loyola University, Maywood, IL 60153.
authors.forename: Patricia
authors.initials: P
authors.lastname: Simms
authors.affiliation: Department of Drug Discovery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Gyda
authors.initials: G
authors.lastname: Beeson
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Christina
authors.initials: C
authors.lastname: Voelkel-Johnson
authors.affiliation: Department of Biostatistics & Epidemiology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.affiliation: Department of Drug Discovery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Beeson
authors.affiliation: Department of Surgery, Loyola University, Maywood, IL 60153.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D064987:Cell- and Tissue-Based Therapy; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; D013438:Sulfhydryl Compounds