Artikel
PD-L2 expression in glioblatoma and its implication for immunotherapy
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Autoren
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Franz Lennard Ricklefs
- Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland; Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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Josie Hayes
- University of California San Francisco, San Francisco, CA, Vereinigte Staaten
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Harald Krenzlin
- Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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Gordon Freeman
- Harvard Medical School, Dana-Farber Institut, Boston, MA, Vereinigte Staaten
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Thomas Sauvigny
- Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland
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Manfred Westphal
- Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland
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Katrin Lamszus
- Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland
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E. Antonio Chiocca
- Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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Sean Lawler
- Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
| Veröffentlicht: | 18. Juni 2018 |
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Gliederung
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Objective: Programmed cell death protein-1 (PD1) expressed on T cells is a key mediator of immune evasion via mediating the inhibition of T-cell function. This occurs via binding of PD1 to either of its ligands PD-L1 and PD-L2 on tumor cells and other cells such as macrophages and microglia in the tumor microenvironment. Immune checkpoint blockade using anti-PD1 antibodies has proven durable clinical benefit in multiple cancer types and is under current investigation in glioblastoma. Tumor PD-L1 expression is often used to screen for tumor susceptibility to anti-PD1 treatment, leading to the assumption that only PD-L1 positive tumors will be included in clinical trials. However, the role of PD-L2 in immune evasion in glioblastoma has not been well studied.
Methods: To assess the roles of PD-L1 and PD-L2 in glioblastoma, their expression was analyzed in TCGA and IVY Atlas RNAseq data in patient tissues and microdissected globlastoma sections respectively. Genes whose expression was correlated with either PD-L1 or PD-L2 were assessed for enrichment in Ingenuity pathways. To compare their effects on patient outcome, Cox regression models for PD-L1 and PD-L2 were fitted. To confirm these findings on both an RNA and protein level, western blot and qPCR gene expression was conducted with glioma-patient derived cell cultures (n= 19) and fresh tumor samples (n=9).
Results: Here we show that PD-L2 is present in glioblastoma at higher levels than PD-L1, and that the level of PD-L2 in the tumor impacts patient survival. Furthermore PD-L2 expression negatively correlated with KPS rho= -0.13 (p=0.007) while age correlated slightly (rho = 0.1, p=0.017). We show that PD-L2 correlates with retinoic acid receptor and viral induction of apoptosis pathways in glioblastoma. Western blot and gene expression analysis of patient tumor samples and patient-derived cell lines shows that PD-L2 is robustly expressed, while PD-L1 expression is variable. Furthermore PD-L2 expression was inducible by IFNy in certain cell lines.
Conclusion: These results suggest that PD-L2 should be considered as a biomarker for eligibility of patients in clinical trials for anti-PD1 therapies and widens the net for patient recruitment in these trials.
