title: Preferential cell death of CD8+ effector memory (CCR7-CD45RA-) T cells by hydrogen peroxide-induced oxidative stress.
abstract: T cells are used in many cell-based cancer treatments. However, oxidative stress that is induced during various chronic inflammatory conditions, such as cancer, can impair the immune system and have detrimental effects on T cell function. In this study, we have investigated the sensitivity of different human T cell subsets to H(2)O(2)-induced oxidative stress. We showed that central memory (CD45RA(-)CCR7(+)) and effector memory (CD45RA(-)CCR7(-)) T cells are more sensitive to H(2)O(2) as compared with naive (CD45RA(+)CCR7(+)) T cells. Furthermore, the study showed that CD8(+) effector memory T cells are more sensitive to low levels of H(2)O(2) (5 microM) compared with other types of T cells investigated. H(2)O(2)-exposed CD45RO(+) T cells showed mitochondrial depolarization prior to caspase 3 activity. Moreover, the pan-caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone rescued cells from death. These experiments suggest that H(2)O(2)-induced cell death of CD45RO(+) T cells acts via the mitochondrial pathway and that caspase involvement is needed. This study suggests that oxidative stress in cancer patients can be disadvantageous for T cell-based adoptive cell transfer therapies, since effector memory T cells are the primary phenotype of the cells administered.
authors.affiliation: Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takahashi
authors.forename: Mikael G V
authors.initials: MG
authors.lastname: Hanson
authors.forename: Håkan R
authors.initials: HR
authors.lastname: Norell
authors.forename: Aleksandra Mandic
authors.initials: AM
authors.lastname: Havelka
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.forename: Rolf V R
authors.initials: RV
authors.lastname: Kiessling
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects; D007425:Intracellular Membranes / Q000187:drug effects; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008564:Membrane Potentials / Q000187:drug effects / Q000276:immunology; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D010539:Permeability / Q000187:drug effects; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C515370:CCR7 protein, human; D061945:Caspase Inhibitors; D006131:Growth Inhibitors; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D006861:Hydrogen Peroxide; D017493:Leukocyte Common Antigens