Sarah T Garber1, Yuuri Hashimoto1, Shiao-Pei Weathers1, Joanne Xiu1, Zoran Gatalica1, Roel G W Verhaak1, Shouhao Zhou1, Gregory N Fuller1, Mustafa Khasraw1, John de Groot1, Sandeep K Reddy1, David Spetzler1, Amy B Heimberger2. 1. Department 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.). 2. Department 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.) aheimber@mdanderson.org.
Abstract
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.
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.
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