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* Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden; and
Department of Surgery and
Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425
Patients with diseases characterized by chronic inflammation, caused by infection or cancer, have T cells and NK cells with impaired function. The underlying molecular mechanisms are diverse, but one of the major mediators in this immune suppression is oxidative stress caused by activated monocytes, granulocytes, or myeloid-derived suppressor cells. Reactive oxygen species can seriously hamper the efficacy of active immunotherapy and adoptive transfer of T and NK cells into patients. In this study, we have evaluated whether enhanced expression of the antioxidant enzyme catalase in human T cells can protect them against reactive oxygen species. Human CD4+ and CD8+ T cells retrovirally transduced with the catalase gene had increased intracellular expression and activity of catalase. Catalase transduction made CD4+ T cells less sensitive to H2O2-induced loss-of-function, measured by their cytokine production and ability to expand in vitro following anti-CD3 stimulation. It also enhanced the resistance to oxidative stress-induced cell death after coculture with activated granulocytes, exposure to the oxidized lipid 4-hydroxynonenal, or H2O2. Expression of catalase by CMV-specific CD8+ T cells saved cells from cell death and improved their capacity to recognize CMV peptide-loaded target cells when exposed to H2O2. These findings indicate that catalase-transduced T cells potentially are more efficacious for the immunotherapy of patients with advanced cancer or chronic viral infections.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants to R.K. from the Swedish Cancer Society, the Swedish Medical Research Council, the Cancer Society of Stockholm, and by a grant to M.N. from the National Institutes of Health, Grant CA102280.
2 T.A. and K.M. contributed equally to this article.
3 Address correspondence and reprint requests to Dr. Rolf Kiessling, Department of Oncology and Pathology, Immune and Gene Therapy Laboratory, Cancer Center Karolinska, R8:01, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail address: Rolf.Kiessling{at}ki.se
4 Abbreviations used in this paper: ROS, reactive oxygen species; HVA, 3-methoxy-4-hydroxyphenyl acetic acid; HNE, (E)-4-hydroxynonenal; 7-AAD, 7-aminoactinomycin D; DC, dendritic cell; LTR, long terminal repeat; PS, penicillin-streptomycin; REP, rapid expansion protocol; MDSC, myeloid-derived suppressor cell.
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