Abstract
ABSTRACT The time-sequential change in immune-related gene expression of the glioblastoma cell line after irradiation was evaluated to speculate the effect of combined immunotherapy with radiotherapy. The U373 MG glioblastoma cell line was irradiated with 6 Gy single dose. Next-generation sequencing (NGS) transcriptome data was generated before irradiation (control), and at 6, 24, and 48 h post-irradiation. Immune-related pathways were analyzed at each time period. The same analyses were also performed for A549 lung cancer and U87 MG glioblastoma cell lines. Western blotting confirmed the programmed death-ligand 1 (PD-L1) expression levels over time. In the U373 MG cell line, neutrophil-mediated immunity, type I interferon signaling, antigen cross-presentation to T cell, and interferon-γ signals began to increase significantly at 24 h and were upregulated until 48 h after irradiation. The results were similar to those of the A549 and U87 MG cell lines. Without T cell infiltration, PD-L1 did not increase even with upregulated interferon-γ signaling in cancer cells. In conclusions, in the glioblastoma cell line, immune-related signals were significantly upregulated at 24 and 48 h after irradiation. Therefore, the time interval between daily radiotherapy might not be enough to expect full immune responses by combined immune checkpoint inhibitors and newly infiltrating immune cells after irradiation.
Highlights
Both phase III studies of nivolumab, an immune checkpoint inhibitor of programmed death-1 (PD-1) plus radiotherapy in newly diagnosed glioblastoma (CheckMate-548 (NCT02667587) and − 498(NCT02617589)) failed to meet primary endpoint[1]
We examined the time-sequential change of immune-related pathways after irradiation in glioblastoma to estimate the effect of combined immuno-radiotherapy
We mainly focused on speculating the optimal time points for combining radiotherapy and anti-PD-(L)1 treatment
Summary
Both phase III studies of nivolumab, an immune checkpoint inhibitor of programmed death-1 (PD-1) plus radiotherapy in newly diagnosed glioblastoma (CheckMate-548 (NCT02667587) and − 498(NCT02617589)) failed to meet primary endpoint[1]. In these trials, patients received nivolumab every two weeks in addition to radiotherapy, and every four weeks. Recent studies reported that neoadjuvant nivolumab two weeks before surgery in recurrent glioblastoma was successful, the sample size was small[2]. Immunotherapy for glioblastoma is still in the investigation phase
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