Lack of p53 Augments Anti-Tumor Functions In Cytolytic T Cells Journal Article

Authors: Banerjee, A; Thyagarajan, K.; Chatterjee, S; Chakraborty, P.; Kesarwani, P.; Soloshchenko, M.; Hommrani, M. A.; Andrijauskaite, K.; Moxley, K.; Janakiraman, H.; Scheffel, M. J.; Helke, K.; Armeson, K.; Palanisamy, V.; Rubinstein, M. P.; Garrett-Mayer, E; Cole, D. J.; Paulos, C. M.; Voelkel-Johnson, C; Nishimura, M. I.; Mehrotra, S
Article Title: Lack of p53 Augments Anti-Tumor Functions In Cytolytic T Cells
Abstract: Repetitive stimulation of T cell receptor (TCR) with cognate antigen results in robust proliferation and expansion of the T cells, and also imprints them with replicative senescence signatures. Our previous studies have shown that life-span and anti-tumor function of T cells can be enhanced by inhibiting reactive oxygen species (ROS) or intervening with ROS dependent JNK activation that leads to its activation induced cell death (AICD). Since tumor suppressor protein p53 is also a redox active transcription factor that regulates cellular ROS generation that triggers downstream factor mediating apoptosis, we determined if p53 levels could influence persistence and function of tumor reactive T cells. Using h3T TCR transgenic mice, with human tyrosinase epitope reactive T cells developed on p53 knock-out (KO) background, we determined its role in regulating anti-tumor T cell function. Our data shows that as compared to h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFN-gamma secretion, cytolytic capacity, expression of stemness gene signature and decreased TGF-beta signaling. This increased effector function correlated to the improved control of subcutaneously established murine melanoma after adoptive transfer of p53-KO T cells . Pharmacological inhibition of human TCR transduced T cells using a combination of p53 inhibitors also potentiated the T cell effector function and improved persistence. Thus, our data highlights the key role of p53 in regulating the tumor reactive T cell response and that targeting this pathway could have potential translational significance in adoptive T cell therapy.
Journal Title: Cancer research
ISSN: 1538-7445; 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2016
Language: ENG
Notes: LR: 20160728; CI: Copyright (c)2016; JID: 2984705R; 2016/07/08 [accepted]; 2015/07/02 [received]; aheadofprint