Crosslink between Temozolomide and PD-L1 immune-checkpoint inhibition in glioblastoma multiforme.
Antineoplastic Agents, Alkylating
/ pharmacology
B7-H1 Antigen
/ genetics
Brain Neoplasms
/ genetics
Cell Line, Tumor
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
/ drug effects
Glioblastoma
/ genetics
Humans
Immunohistochemistry
Interferon-gamma
/ pharmacology
Phosphorylation
/ drug effects
STAT Transcription Factors
/ genetics
Signal Transduction
/ drug effects
Temozolomide
/ pharmacology
Tumor Cells, Cultured
PD-L1 immunotherapy
Recurrent GBM
Temozolomide
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
01 Feb 2019
01 Feb 2019
Historique:
received:
23
07
2018
accepted:
17
01
2019
entrez:
3
2
2019
pubmed:
3
2
2019
medline:
31
8
2019
Statut:
epublish
Résumé
In recent years, PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM). Based on the results of our earlier work, which showed a reduction of PD-L1 expression in patients treated with temozolomide (TMZ), we aimed to investigate the link between TMZ therapy and the immune control point target PD-L1. RNA-sequencing data from de-novo and recurrent glioblastoma were analyzed by AutoPipe algorithm. Results were confirmed either in a cell model by two primary and one established GBM cell line and specimens of de-novo and recurrent GBM. PD-L1 and pathway activation of the JAK/STAT pathway was analyzed by quantitative real-time PCR and western blot. We found a significant downregulation of the JAK/STAT pathway and immune response in recurrent tumors. The cell model showed an upregulation of PD-L1 after IFNγ treatment, while additional TMZ treatment lead to a reduction of PD-L1 expression and JAK/STAT pathway activation. These findings were confirmed in specimens of de-novo and recurrent glioblastoma. Our results suggest that TMZ therapy leads to a down-regulation of PD-L1 in primary GBM cells. These results support the clinical findings where PD-L1 is significantly reduced in recurrent GBMs. If the target is diminished, it may also lead to impaired efficacy of PD-1/PD-L1 inhibitors such as nivolumab.
Sections du résumé
BACKGROUND
BACKGROUND
In recent years, PD-1/PD-L1 immune checkpoint inhibitors have improved cancer therapy in many tumor types, but no benefit of immune checkpoint therapy has been found in glioblastoma multiforme (GBM). Based on the results of our earlier work, which showed a reduction of PD-L1 expression in patients treated with temozolomide (TMZ), we aimed to investigate the link between TMZ therapy and the immune control point target PD-L1.
METHODS
METHODS
RNA-sequencing data from de-novo and recurrent glioblastoma were analyzed by AutoPipe algorithm. Results were confirmed either in a cell model by two primary and one established GBM cell line and specimens of de-novo and recurrent GBM. PD-L1 and pathway activation of the JAK/STAT pathway was analyzed by quantitative real-time PCR and western blot.
RESULTS
RESULTS
We found a significant downregulation of the JAK/STAT pathway and immune response in recurrent tumors. The cell model showed an upregulation of PD-L1 after IFNγ treatment, while additional TMZ treatment lead to a reduction of PD-L1 expression and JAK/STAT pathway activation. These findings were confirmed in specimens of de-novo and recurrent glioblastoma.
CONCLUSIONS
CONCLUSIONS
Our results suggest that TMZ therapy leads to a down-regulation of PD-L1 in primary GBM cells. These results support the clinical findings where PD-L1 is significantly reduced in recurrent GBMs. If the target is diminished, it may also lead to impaired efficacy of PD-1/PD-L1 inhibitors such as nivolumab.
Identifiants
pubmed: 30709339
doi: 10.1186/s12885-019-5308-y
pii: 10.1186/s12885-019-5308-y
pmc: PMC6359796
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
B7-H1 Antigen
0
CD274 protein, human
0
STAT Transcription Factors
0
Interferon-gamma
82115-62-6
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
117Subventions
Organisme : German Cancer Society
ID : Seeding Grand TII
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