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 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.

Human IL4I1 is a secreted l-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation

“…Memory T lymphocytes were also more sensitive to the presence of H 2 O 2 and phenylpyruvate than naive T lymphocytes. These results, obtained with H 2 O 2 , are in accordance with a previous report, 16 whereas to date phenylpyruvate is known only for its toxicity toward neural cells. 28 However, the effects of H 2 O 2 were observed at micromolar doses, while those of phenylpyruvate required millimolar amounts and thus are less likely to be compatible with a physiological effect.…”

“…Short exposure to H 2 O 2 decreases TCR chain expression and tyrosine phosphorylation, ultimately resulting in the suppression of antigen-specific T-cell proliferative responses 15 and cytokine secretion 29 without affecting viability, while prolonged treatment with H 2 O 2 induces T-cell apoptosis. 16 In our experimental setting, we observed a transient decrease in TCR chain expression in the absence of apoptosis. The brief production of H 2 O 2 due to the rapid loss of activity of hIL4I1-coated beads in culture medium (data not shown) may explain these results along with the fact that incubation of T cells with hIL4I1 for 24 hours did not increase its effect compared with a 3 hours incubation.…”

Dopamine targets cycling B cells independent of receptors/transporter for oxidative attack: Implications for non-Hodgkin’s lymphoma

“…Chen et al (35) were unable to determine a basis for the selectivity of ascorbate͞H 2 O 2 for cancer cells, but a similarly restricted profile has been described both by us here and, significantly, for L-DOPA against stimulated vs. resting lymphocytes and nononcogenic 3T3-fibroblasts (36). Also relevant is the observation that CD45ROϩ T cells are killed preferentially by H 2 O 2 (IC 50 ϭ 5-10 M) compared with generally noncycling CD45RAϩ counterparts (37). Taken together, the different studies underscore an exquisite, yet unexplained, sensitivity of proliferating lymphocytes, malignant or otherwise, to cellular assault from reactive metabolites of H 2 O 2 and its precursors.…”

Coexpressed Catalase Protects Chimeric Antigen Receptor–Redirected T Cells as well as Bystander Cells from Oxidative Stress–Induced Loss of Antitumor Activity

“…This is particularly of clinical relevance in the setting of adoptive cell therapy where the transplanted T cells are thousand fold expanded ex vivo prior to transfer and entering the tumor tissues. T cell subsets are differentially affected by ROS, with CD8 + T effector memory cells being particularly more susceptible to ROS-induced cell death and loss in function than are their naive T cell counterparts (21). These memory cells are essential for providing a better clinical outcome in CRC patients (42).…”

“…High concentrations of ROS can lead to necrotic cell death, although there is a window of ROS-induced oxidative stress in which lymphocytes are still viable but become unresponsive (18). This has been linked to blockage of NF-kB activation due to protein oxidation, resulting in deficient IFN-g, TNF-a, and IL-2 production (20,21). ROS-induced alterations in T cell and NK cell functions may also be attributed to the decreased TCRz-and CD16z-chain levels found in tumor-bearing patients and mice (22)(23)(24), which is associated with tumor accumulation of myeloid cells (25).…”