Recognition by natural killer cells of N6‐isopentenyladenosine‐treated human glioma cell lines

Abstract

Cancer cell stress induced by cytotoxic agents promotes antitumor immune response. Here, we observed that N6-isopentenyladenosine (iPA), an isoprenoid modified adenosine with a well established anticancer activity, was able to induce a significant upregulation of cell surface expression of natural killer (NK) cell activating receptor NK Group 2 member D (NKG2D) ligands on glioma cells in vitro and xenografted in vivo. Specifically suboptimal doses of iPA (0.1 and 1 mM) control the selective upregulation of UL16-binding protein 2 on p53wt-expressing U343MG and that of MICA/B on p53mut-expressing U251MG cells. This event made the glioblastoma cells a potent target for NK cell-mediated recognition through a NKG2D restricted mechanism. p53 siRNA-mediated knock-down and pharmacological inhibition (pifithrin-a), profoundly prevented the iPA action in restoring the immunogenicity of U343MG cells through a mechanism that is dependent upon p53 status of malignancy. Furthermore, accordingly to the preferential recognition of senescent cells by NK cells, we found that iPA treatment was critical for glioma cells entry in premature senescence through the induction of S and G2/M phase arrest. Collectively, our results indicate that behind the well established cytotoxic and antiangiogenic effects, iPA can also display an immune-mediated antitumor activity. The indirect engagement of the innate immune system and its additional activity in primary derived patient's glioma cell model (GBM17 and GBM37), fully increase its translational relevance and led to the exploitation of the isoprenoid pathway for a valid therapeutic intervention in antiglioma research.

N6-Isopentenyladenosine Enhances the Radiosensitivity of Glioblastoma Cells by Inhibiting the Homologous Recombination Repair Protein RAD51 Expression

“…Moreover, the anti-apoptotic BCL2 protein, which was upregulated by IR treatment, was remarkably downregulated by combined treatment with iPA in both U251MG and U343MG cells. Interestingly, iPA+IR combined treatment reduced also the protein levels of NFkB (Figure 2, Supplementary Information), the activation of which, following DNA damage, emerged as a key mediator of cancer resistance to genotoxic agents (16). Overall, iPA likely lowered the apoptotic threshold of glioblastoma cells acting on different antiapoptotic players.…”

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

“…Upon receptor activation, NK cells can then specifically induce the death of senescent cells through their cytolytic machinery. Remarkably, a role for NK cells in the immune surveillance of senescent cells has been pointed out in liver fibrosis, HCC, multiple myeloma (MM), and glioma cells stressed by dysregulation of the mevalonate pathway …”

“…Age is a strong predictive factor in the occurrence of glioma, the most aggressive adult brain cancer . Little is known about how aging increases glioma malignancy but recent studies highlighted the contribution of a pool of dysregulated NPCs with an increased tendency to undergo senescence as opposed to proliferation and self‐renewal in response to growth signals.…”

Prediction and identification of novel HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from endocan

“…Recently, the immune system has been proved to recognize and eliminate the spontaneous development of glioma cells [28][29][30]. Because of its potential to manipulate and attack tumor cells, immunotherapy represents promising strategy in the clinic [31][32][33].…”