Inhibition of Superoxide Generation upon T-Cell Receptor Engagement Rescues Mart-127-35-Reactive T Cells from Activation-Induced Cell Death

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 15; pp. 6282 - 6289
• Main Authors: NORELL, Hakan, DA PALMA, Telma Martins, NISHIMURA, Michael I, MUKHERJI, Bijay, MEHROTRA, Shikhar, LECHER, Aaron, KAUR, Navtej, MEHROTRA, Meenal, NAGA, Osama S, SPIVEY, Natalie, OLAFIMIHAN, Seye, CHAKRABORTY, Nitya G, VOELKEL-JOHNSON, Christina
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-2009
• Subjects: Antineoplastic agents; Biological and medical sciences; Medical sciences; Pharmacology. Drug treatments; Tumors; Regulation(control); Hyperoxides; T cell receptor; Cell death; T-Lymphocyte; Activation; Inhibitor; Inhibition; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1176

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-127-35–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-γ. 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-127-35–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]