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Preferential Cell Death of CD8⁺ Effector Memory (CCR7^–CD45RA^–) T Cells by Hydrogen Peroxide-Induced Oxidative Stress ¹

Akihiro Takahashi^2,*, Mikael G. V. Hanson^2,*, Håkan R. Norell^*, Aleksandra Mandic Havelka^*, Koji Kono, Karl-Johan Malmberg and Rolf V. R. Kiessling^3,*

^* Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden; First Department of Surgery, University of Yamanashi, Yamanashi, Japan; and Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

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 H₂O₂-induced oxidative stress. We showed that central memory (CD45RA^–CCR7⁺) and effector memory (CD45RA^–CCR7^–) T cells are more sensitive to H₂O₂ 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 H₂O₂ (5 µM) compared with other types of T cells investigated. H₂O₂-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 H₂O₂-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.

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