Lack ofp53Augments 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 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-γ 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 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.

Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection

“…Data are presented as the ratio (fold-change) between MFI (Median fluorescence intensity) of H3K9me2 CD8+ T cells detected in treated vs. untreated cultures from individual patients; statistical analysis was performed with the Wilcoxon signed-rank test; columns and dots represent median values and single patients, respectively. relevance of our model to other T cell exhaustion-associated pathologies, including cancer, is further corroborated by the increased effector function and enhanced glycolytic commitment exhibited by T cells derived from p53 knock-out mice 53 . In the same model, adoptive transfer of p53 knock-out T cells has been shown to improve the control of a subcutaneously established murine melanoma, thus highlighting a key role of p53 in modulating tumor-reactive T-cell responses with a potential translational significance in adoptive T-cell therapy 53 .…”

Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death

“…The pharmacological inhibition of p53 can protect activated T cells from death following TCR restimulation (11), and we have recently demonstrated that T cells from p53-knockout mice are likewise protected from AICD (26). However, the activation status of p53 has not previously been investigated.…”

p53, cancer and the immune response

“…Indeed, enhanced growth of tumours in p53-null hosts is likely to reflect, to some extent, the consequences of loss of p53 in the immune cells. Therefore, in order to dissect the role of p53 in various immune compartments, genetic alterations of p53 in monocytes, pan myeloid lineages and T cells have been investigated (Banerjee et al, 2016;He et al, 2015;Sharma et al, 2018) (Fig. 4).…”

“…4). Furthermore, genetic deletion of p53 in antigen-specific T cells increases their metabolic fitness and reduces human melanoma growth in xenograft models (Banerjee et al, 2016) (Fig. 4).…”