Programmed death ligand 1 in glioblastoma

Programmed death ligand 1 in glioblastoma

Reports of programmed death ligand 1 (PD-L1) expression in glioblastoma are highly variable (ranging from 6% to 88%) and its role as a prognostic marker has yielded conflicting results.

Data points to a putative role for PD-L1 expression in glioblastoma biology, which correlates to poor patient overall survival, as well as with a general systemic inflammatory status and immunosuppression 1).

A 5% PD-L1 expression cut-off identified a subset of glioblastoma that is associated with a worse clinical outcome. This association remained significant within the newly defined IDH wildtype classification. These findings could have implications for patient stratification in future clinical trials of PD-1/PD-L1 blockade 2).


For patients receiving Dendritic cell vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1+/CD8+ ratio, with gross tumor resection, and receiving CCRT 3).


In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in > 5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase 1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3)-positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan-Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P = 0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P = 0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P = 0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P < 0.001 and P = 0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P < 0.001), and IDH-1 wild type status (P = 0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis 4).


Immunotherapies for glioblastoma multiforme including PD1/PD-L1 inhibition are currently tested in ongoing clinical trials. The purpose of a study was to investigate the molecular background of PD-L1 expression in glioblastoma multiforme and to find associated pathway activation and genetic alterations. Heiland et al., show that PD-L1 is up-regulated in IDH1/2 wildtype glioblastoma multiforme compared to lower-grade gliomas. In addition, a strong association of PD-L1 with the mesenchymal expression subgroup was observed. Consistent with that, NF1 mutation and corresponding activation of the MAPK pathway was strongly connected to PD-L1 expression. The findings may explain different response to PD-L1 inhibition of patients in ongoing trials and may help to select patients that may profit of immunotherapy in the future 5).


1)

Noronha C, Ribeiro AS, Taipa R, Leitão D, Schmitt F, Reis J, Faria C, Paredes J. PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma. J Neurooncol. 2022 Jan 23. doi: 10.1007/s11060-021-03907-3. Epub ahead of print. PMID: 35066764.
2)

Pratt D, Dominah G, Lobel G, Obungu A, Lynes J, Sanchez V, Adamstein N, Wang X, Edwards NA, Wu T, Maric D, Giles AJ, Gilbert MR, Quezado M, Nduom EK. Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma. Neurosurgery. 2018 Jul 12. doi: 10.1093/neuros/nyy268. [Epub ahead of print] PubMed PMID: 30011045.
3)

Jan CI, Tsai WC, Harn HJ, Shyu WC, Liu MC, Lu HM, Chiu SC, Cho DY. Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme. Front Immunol. 2018 May 29;9:727. doi: 10.3389/fimmu.2018.00727. eCollection 2018. PubMed PMID: 29910795; PubMed Central PMCID: PMC5992384.
4)

Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, Kim CY, Lee HS, Choe G. Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. J Neurooncol. 2018 Feb;136(3):453-461. doi: 10.1007/s11060-017-2675-6. Epub 2017 Nov 16. PubMed PMID: 29147863.
5)

Heiland DH, Haaker G, Delev D, Mercas B, Masalha W, Heynckes S, Gäbelein A, Pfeifer D, Carro MS, Weyerbrock A, Prinz M, Schnell O. Comprehensive analysis of PD-L1 expression in glioblastoma multiforme. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15031. [Epub ahead of print] PubMed PMID: 28178682.

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