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Inhibition of Superoxide Generation upon T-Cell Receptor Engagement Rescues Mart-1_27-35–Reactive T Cells from Activation-Induced Cell Death

Departments of ¹ Surgery, ² Microbiology and Immunology, and ³ Pathology, Medical University of South Carolina, Charleston, South Carolina and ⁴ Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut

Requests for reprints: Shikhar Mehrotra, Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425. Phone: 843-792-9195; Fax: 843-792-2556; E-mail: mehrotr{at}musc.edu.

Key Words: AICD • CTL • Oxidative stress • ROS • JNK

Cytotoxic T lymphocytes (CTL) may undergo massive expansion upon appropriate antigenic stimulation. Homeostasis is maintained by a subsequent "contraction" of these cells. Activation-induced cell death (AICD) and programmed cell death prevent the untoward side effects, arising from excessive numbers and prolonged persistence of activated CTL, that occur upon uncontrolled and/or continued expansion. However, effector cell persistence has been identified as a hallmark of successful T-cell–mediated adoptive immunotherapy. Thus, prevention of AICD may be critical to achieve more successful clinical results. We have previously shown that treatment with the c-Jun NH₂-terminal kinase (JNK) inhibitor SP600125 protects human melanoma epitope Mart-1_27-35–reactive CTL from apoptotic death upon their reencounter with cognate antigen. However, inhibition of JNK also interferes with the functional ability of the CTL to secrete IFN-. Here, we show that reactive oxygen species (ROS) inhibitors, such as the superoxide dismutase mimetic Mn (III) tetrakis (5, 10, 15, 20-benzoic acid) porphyrin (MnTBAP), efficiently protected Mart-1_27-35–reactive primary CTL from AICD without impairing their functional capability. MnTBAP prevented the increase in intracellular ROS, mitochondrial membrane collapse, and DNA fragmentation observed in control-treated cells upon cognate antigen encounter. Furthermore, the mechanism of AICD prevention in primary CTL included blockade of JNK activation. Finally, tumor-reactive in vitro expanded tumor infiltrating lymphocytes, which are used clinically in cancer immunotherapy, also benefit from MnTBAP-mediated antioxidant treatment. Thus, modulation of the redox pathway might improve CTL persistence and lead to better clinical results for T cell–based immunotherapies. [Cancer Res 2009;69(15):6282–9]