Inhibition of Superoxide Generation upon TCR 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, Håkan, da Palma, Telma Martins, Lesher, Aaron, Kaur, Navtej, Mehrotra, Meenal, Naga, Osama S., Spivey, Natalie, Olafimihan, Seye, Chakraborty, Nitya G., Voelkel-Johnson, Christina, Nishimura, Michael I., Mukherji, Bijay, Mehrotra, Shikhar
• Format: Journal Article
• Language: English
• Published: 28-07-2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-1176

Cytolytic T lymphocytes (CTL) 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 c-jun N-terminal kinase (JNK)-inhibitor, SP600125, protects human melanoma epitope Mart-1
27-35
reactive CTL from apoptotic death upon their re-encounter with cognate antigen. However, inhibition of JNK also interferes with the functional capability of the CTL to secrete interferon (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-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.