Cancer cells are originated from normal cells that have acquired numerous hallmark abilities that allow them to become malignant; thus, they are essentially identified as ?self?-part of the host. Cancer cells take advantage of this nature ability by exploiting various immune escape mechanisms to persist despite anticancer treatment. The involvement of p53 in post-apoptosis has not been implicated until now. We identified a post-apoptotic target gene of p53, Death Domain1? (DD1?) that is highly responsive to genotoxic stresses, induced in apoptotic cells, and expressed in immune cells. DD1? has similarity with several members of the immunoglobulin superfamily with the IgV domain, including TIM family proteins and immune-checkpoint modulators PD-1 and PD-L1. Moreover, we found that PD-L1 and PD-1 are also up-regulated in response to genotoxic stress in a p53-dependent manner. Of importance, we have also found that the DD1?-PD-1 axis (PD1?PD-L1 and PD-1?PD-L2) is characterized as a potent inhibitor of immune activation, particularly through inhibition of T cell activity. Based on the preliminary data, we propose to investigate that p53-?DD1? mediated activation of such immune checkpoint regulators in response to genotoxic stress contributes to tumor cell survival, thus limiting the full potential of anti-tumor immunity and facilitating relapse, and plays a critical role in the post-apoptotic removal of stress-mediated dead cells in vitro and in vivo. We will also investigate a novel link between p53-dependent DD1?-driven clearance of apoptotic cells and immune tolerance in connection with the PD-L1/PD-1 axis. Therefore, we propose that p53-dependent activation of immune checkpoint regulators may extend the repertoire of p53 activities to ?Guardian of the Immune integrity?.
This research will provide important knowledge of the mechanisms that cause resistance to chemotherapy. It will also identify better therapies to prevent the occurrence of resistance during initial anti-cancer drug treatment with wt-p53, by developing combination therapies with checkpoint blockade immunotherapies such as antibodies targeting DD1?, PD-L1, and/or PD-1.
|Muñoz-Fontela, César; Mandinova, Anna; Aaronson, Stuart A et al. (2016) Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol 16:741-750|