Downregulation of PD-L1 via FKBP5 by celecoxib augments antitumor effects of PD-1 blockade in a malignant glioma model

Abstract

Background Antitumor therapies targeting programmed cell death-1 (PD-1) or its ligand-1 (PD-L1) are used in various cancers. However, in glioblastoma (GBM), the expression of PD-L1 varies between patients, and the relationship between this variation and the efficacy of anti-PD-1 antibody therapy remains unclear. High expression levels of PD-L1 affect the proliferation and invasiveness of GBM cells. As COX-2 modulates PD-L1 expression in cancer cells, we tested the hypothesis that the COX-2 inhibitor celecoxib potentiates anti-PD-1 antibody treatment via the downregulation of PD-L1. Methods Six-week-old male C57BL/6 mice injected with murine glioma stem cells (GSCs) were randomly divided into four groups treated with vehicle, celecoxib, anti-PD-1 antibody, or celecoxib plus anti-PD-1 antibody and the antitumor effects of these treatments were assessed. To verify the mechanisms underlying these effects, murine GSCs and human GBM cells were studied in vitro. Results Compared with that with each single treatment, the combination of celecoxib and anti-PD-1 antibody treatment significantly decreased tumor volume and prolonged survival. The high expression of PD-L1 was decreased by celecoxib in the glioma model injected with murine GSCs, cultured murine GSCs, and cultured human GBM cells. This reduction was associated with post-transcriptional regulation of the co-chaperone FK506-binding protein 5 (FKBP5). Conclusions Combination therapy with anti-PD-1 antibody plus celecoxib might be a promising therapeutic strategy to target PD-L1 in glioblastoma. The downregulation of highly-expressed PD-L1 via FKBP5, induced by celecoxib, could play a role in its antitumor effects.

Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NF-κB/MDR1 pathway

“…According to our previous study 6 , cells or tissue samples were homogenized in RIPA buffer containing a protease/phosphatase inhibitor cocktail (Cell Signaling Technology, CST, 5872). After 10-min centrifugation at 12,000 rpm, 4 °C, the protein concentration in the supernatants was determined using BCA kit (Thermo Fisher Scientific, USA).…”

“…Furthermore, tumor cells acquire chemo-resistance during treatment, thus deterring GBM treatment. Though various approaches including neoadjuvant anti-PD-1 immunotherapy have been studied 5 , 6 , novel therapeutic strategies are required to improve the prognosis of GBM patients.…”

Celecoxib as a Valuable Adjuvant in Cutaneous Melanoma Treated with Trametinib

“…Consequently, selective COX-2 inhibitors can be considered as promising cancer chemo-preventive agents. Among them, celecoxib has been proven to be efficient adjuvant in melanoma, despite its incompletely understood antitumor mechanisms [ 20 , 21 ].…”

DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma

“…In several human cancer tissues, a relevant role for FKBP5 in sustaining cancer cell growth and aggressiveness has been documented. In particular, for glioma [ 28 ], prostate cancer and melanoma [ 29 ] a strict correlation between protein abundance and aggressiveness has been demonstrated.…”