gms | German Medical Science

69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

03.06. - 06.06.2018, Münster

PD-L2 expression in glioblatoma and its implication for immunotherapy

Meeting Abstract

  • Franz Lennard Ricklefs - Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland; Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Josie Hayes - University of California San Francisco, San Francisco, CA, Vereinigte Staaten
  • Harald Krenzlin - Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Gordon Freeman - Harvard Medical School, Dana-Farber Institut, Boston, MA, Vereinigte Staaten
  • Thomas Sauvigny - Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland
  • Manfred Westphal - Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland
  • Katrin Lamszus - Universitätsklinikum Hamburg-Eppendorf, Neurochirurgie, Hamburg, Deutschland
  • E. Antonio Chiocca - Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
  • Sean Lawler - Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten

Deutsche Gesellschaft für Neurochirurgie. 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie. Münster, 03.-06.06.2018. Düsseldorf: German Medical Science GMS Publishing House; 2018. DocV265

doi: 10.3205/18dgnc283, urn:nbn:de:0183-18dgnc2837

Published: June 18, 2018

© 2018 Ricklefs et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

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.