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Published on: November 28, 2015
Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies
Sarah T Garber1, Yuuri Hashimoto1, Shiao-Pei Weathers1
1Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (S.T.G., Y.H., A.B.H.); Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (S.-P.W., J.d.G.); Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (R.G.W.V.); Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (S.Z.); Department of Neuropathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA (G.N.F.); Caris Life Sciences, Phoenix, Arizona, USA (J.X., Z.G., S.K.R., D.S.); The University of Sydney, Sydney, Australia (M.K.).
Background:
Expression of programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) across glioma grades is undocumented, and their interactions with commonly expressed genetic and epigenetic alterations are undefined but nonetheless highly relevant to combinatorial treatments.
Methods:
Patients with CNS malignancies were profiled by Caris Life Sciences from 2009 to 2016. Immunohistochemistry findings for PD-1 on tumor-infiltrating lymphocytes (TIL) and PD-L1 on tumor cells were available for 347 cases. Next-generation sequencing, pyrosequencing, immunohistochemistry, fragment analysis, and fluorescence in situ hybridization were used to determine isocitrate dehydrogenase 1 (IDH1), phosphatase and tensin homolog (PTEN), and tumor protein 53 mutational status, O(6)-DNA methylguanine-methyltransferase promoter methylation (MGMT-Me) status, PTEN expression, plus epidermal growth factor receptor variant III and 1p/19q codeletion status.
Results:
PD-1+ TIL expression and grade IV gliomas were significantly positively correlated (odds ratio [OR]: 6.363; 95% CI: 1.263, 96.236)-especially in gliosarcomas compared with glioblastoma multiforme (P = .014). PD-L1 expression was significantly correlated with tumor grade with all PD-L1+ cases (n = 21) being associated with grade IV gliomas. PD-1+ TIL expression and PD-L1 expression were significantly correlated (OR: 5.209; 95% CI: 1.555, 20.144). Mutations of PTEN, tumor protein 53, BRAF, IDH1, and epidermal growth factor receptor or MGMT-Me did not associate with increased intratumoral expression of either PD-1+ TIL or PD-L1 in glioblastoma multiforme even before false discovery rate correction for multiple comparison.
Conclusions:
Targeting immune checkpoints in combination with other therapeutics based on positive biomarker selection will require screening of large patient cohorts.
Insights
Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression correlates with higher glioma grades, particularly in gliosarcomas. Understanding these immune checkpoint interactions is crucial for developing targeted combinatorial treatments for brain tumors.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Biology
Background:
- The expression patterns of programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in gliomas of varying grades remain largely undocumented.
- The interplay between PD-1/PD-L1 and common genetic/epigenetic alterations in gliomas is not well-defined, yet it holds significant implications for combinatorial therapeutic strategies.
Purpose of the Study:
- To investigate the expression of PD-1 and PD-L1 in central nervous system (CNS) malignancies.
- To determine the correlation between PD-1/PD-L1 expression and various genetic and epigenetic alterations in glioma patients.
- To explore the potential of PD-1/PD-L1 as biomarkers for combinatorial treatments.
Main Methods:
- Profiling of 347 CNS malignancy cases using immunohistochemistry for PD-1 on tumor-infiltrating lymphocytes (TIL) and PD-L1 on tumor cells.
- Utilizing next-generation sequencing, pyrosequencing, and other molecular techniques to assess mutations (IDH1, PTEN, TP53, EGFRvIII, BRAF), methylation (MGMT-Me), and codeletions (1p/19q).
Main Results:
- PD-1+ TIL expression showed a significant positive correlation with grade IV gliomas, especially gliosarcomas (OR: 6.363).
- PD-L1 expression was exclusively associated with grade IV gliomas (n=21).
- PD-1+ TIL and PD-L1 expression were significantly correlated (OR: 5.209). Common mutations (PTEN, TP53, BRAF, IDH1, EGFR) and MGMT promoter methylation did not associate with increased PD-1 or PD-L1 expression in glioblastoma multiforme.
Conclusions:
- PD-1 and PD-L1 expression are linked to higher-grade gliomas, suggesting their potential as biomarkers.
- Combinatorial immunotherapies targeting immune checkpoints may benefit from biomarker selection strategies.
- Screening large patient cohorts will be essential for developing effective combination treatments based on biomarker status.
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