title: Lack of p53 Augments Antitumor 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 antitumor 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. Because 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 knockout (KO) background, we determined its role in regulating antitumor T-cell function. Our data show that as compared with h3T cells, h3T-p53 KO T cells exhibited enhanced glycolytic commitment that correlated with increased proliferation, IFNγ secretion, cytolytic capacity, expression of stemness gene signature, and decreased TGF-β 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 highlight 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. Cancer Res; 76(18); 5229-40. ©2016 AACR.
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Thyagarajan
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Shilpak
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakraborty
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Pravin
authors.initials: P
authors.lastname: Kesarwani
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Myroslawa
authors.initials: M
authors.lastname: Soloshchenko
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Mazen
authors.initials: M
authors.lastname: Al-Hommrani
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Kristina
authors.initials: K
authors.lastname: Andrijauskaite
authors.affiliation: Department of Surgery, Oncology Institute, Loyola University, Maywood, IL 60153.
authors.forename: Kelly
authors.initials: K
authors.lastname: Moxley
authors.affiliation: Department of Oral Health Research, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Harinarayanan
authors.initials: H
authors.lastname: Janakiraman
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Scheffel
authors.affiliation: Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Kristi
authors.initials: K
authors.lastname: Helke
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Kent
authors.initials: K
authors.lastname: Armenson
authors.affiliation: Department of Oral Health Research, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Palanisamy
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Rubinstein
authors.affiliation: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Elizabeth-Garrett
authors.initials: EG
authors.lastname: Mayer
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cole
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Chrystal M
authors.initials: CM
authors.lastname: Paulos
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC 29425.
authors.lastname: Christina-Voelkel-Johnson
authors.affiliation: Department of Surgery, Oncology Institute, Loyola University, Maywood, IL 60153.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.affiliation: Department of Surgery, Medical University of South Carolina, Charleston, SC 29425.
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53