Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma

Background Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. Methods We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. Results Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. Conclusion TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastom

Coordination Properties of Perfluoroethyl- and Perfluorophenyl-Substituted Phosphonous acids, (RP)-P-f(OH)(2)

Allefeld N, Kurscheid B, Neumann B, Stammler H-G, Ignat'ev N, Hoge B. Coordination Properties of Perfluoroethyl- and Perfluorophenyl-Substituted Phosphonous acids, (RP)-P-f(OH)(2). Chemistry - A European Journal. 2015;21(39):13666-13675.Phosphinic acids, (RP)-P-f(O)(OH)H (R-f=CF3, C2F5, C6F5), turned out to be excellent preligands for the coordination of phosphonous acids, (RP)-P-f(OH)(2). Addition of C2F5P(O)(OH)H to solid PtCl2 under different reaction conditions allows the isolation and full characterization of the mononuclear complexes [ClPt{P(C2F5)(OH)O}{P(C2F5)(OH)(2)}(2)] and [Pt{P(C2F5)(OH)O}(2){P(C2F5)(OH)(2)}] containing hydrogen-bridged [(RP)-P-f(OH)O](-) and (RP)-P-f(OH)(2) units. Further deprotonation of [Pt{P(C2F5)(OH)O}(2){P(C2F5)(OH)(2)}(2)] leads to the formation of the dianionic platinate, [Pt{P(C2F5)(OH)O}(4)](2-), revealing four intramolecular hydrogen bridges. With PdCl2 the dinuclear complex [Pd-2(-Cl)(2){[P(C2F5)(OH)O](2)H}(2)] was isolated and characterized. The Cl- free complex [Pd{P(C2F5)(OH)O}(2){P(C2F5)(OH)(2)}(2)] was also prepared and deprotonated to the dianionic palladate, [Pd{P(C2F5)(OH)O}(4)](2-). Both compounds were characterized by NMR spectroscopy, IR spectroscopy, and X-ray analyses. In addition, the C6F5 derivatives [ClPt{P(C6F5)(OH)O}{P(C6F5)(OH)(2)}(2)] and [Pd-2(-Cl)(2){[P(C6F5)(OH)O](2)H}(2)] as well as the CF3 derivative [Pd-2(-Cl)(2){[P(CF3)(OH)O](2)H}(2)] were synthesized and fully characterized. Phosphonous acid complexes are inert towards air and moisture and can be stored for several months without decomposition. The catalytic activity of the palladium complexes in the Suzuki cross-coupling reaction between 1-bromo-3-fluorobenzene and phenyl boronic acid was demonstrated

Correlation of immune phenotype with IDH mutation in diffuse glioma

BACKGROUND: Tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) are targets of immune checkpoint inhibitors. METHODS: Forty-three World Health Organization (WHO) grade II/III gliomas (39 IDH-mutant [mut], 4 IDH-wildtype [wt]) and 14 IDH-mut glioblastomas (GBM) were analyzed for TIL (CD3+; PD1+) infiltration and PD-L1 expression. Results were compared with the data of a previously published series of 117 IDH-wt glioblastomas. PD-L1 gene expression levels were evaluated in 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database. RESULTS: TIL and PD-L1 expression were observed in approximately half of WHO grade II/III gliomas. IDH-wt status was associated with significantly higher TIL infiltration and PD-L1 expression among all (grades II-IV) cases (n = 174, P < 0.001) and within the cohort of glioblastomas (n = 131, P < 0.001). In low-grade glioma (LGG) and glioblastoma cohorts of TCGA, significantly higher PD-L1 gene expression levels were evident in IDH-wt compared with IDH-mut samples (LGG: N = 516; P = 1.933e-11, GBM: N = 161; P < 0.009). Lower PD-L1 gene expression was associated with increased promoter methylation (Spearman correlation coefficient -0.36; P < 0.01) in the LGG cohort of TCGA. IDH-mut gliomas had higher PD-L1 gene promoter methylation levels than IDH-wt gliomas (P < 0.01). CONCLUSIONS: The immunological tumor microenvironment of diffuse gliomas differs in association with IDH mutation status. IDH-wt gliomas display a more prominent TIL infiltration and higher PD-L1 expression than IDH-mut cases. Mechanistically this may be at least in part due to differential PD-L1 gene promoter methylation levels. Our findings may be relevant for immune modulatory treatment strategies in glioma patients.This study was funded by the research budget of the Medical University of Vienna and a grant by the “Hochschuljubuläumsstiftung” with the project title “Das Immunsystem im Kampf gegen Krebs” and the Swiss National Science Foundation 31003A_163297