Carolina Noronha1,2, Ana Sofia Ribeiro2, Ricardo Taipa3,4, Dina Leitão5, Fernando Schmitt2, Joaquim Reis1,6, Cláudia Faria7,8, Joana Paredes9,10. 1. Neurosurgery Department, Hospital de Santo Antonio, Centro Hospitalar Universitario do Porto, Porto, Portugal. 2. i3S- Institute for Investigation and Innovation in Health, Porto, Portugal. 3. Neuropathology Unit, Hospital de Santo Antonio, Centro Hospitalar Universitario do Porto, Porto, Portugal. 4. Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal. 5. Faculty of Medicine, University of Porto, Porto, Portugal. 6. Anatomy Department, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal. 7. Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, Lisboa, Portugal. 8. IMM - Instituto de Medicina Molecular João Lobo Antunes, Lisboa, Portugal. 9. i3S- Institute for Investigation and Innovation in Health, Porto, Portugal. jparedes@ipatimup.pt. 10. Faculty of Medicine, University of Porto, Porto, Portugal. jparedes@ipatimup.pt.
Abstract
PURPOSE: Glioblastoma is the most common primary malignant brain tumor in the adult, whose grim prognosis largely relates to the absence of effective treatment targets. Given its success in other cancers, immunotherapy has been trialed in glioblastoma and failed to demonstrate the expected benefit. Importantly, these disappointing results highlight the importance of understanding the unique and transforming biology of glioblastoma and its microenvironment. Our goal was to evaluate and characterize the expression of PD-L1 through immunohistochemistry in a large glioblastoma cohort. We further studied PD-L1 expression-associated prognosis and its correlation to systemic and neuropathological parameters. METHODS: A series of 352 glioblastoma specimens (313 initial resection, 39 matched recurrences) was collected, with a detailed characterization of tumor neuropathological characteristics, including the presence, density and location of tumor infiltrating lymphocytes (TIL). Two hematological markers, absolute lymphocyte count and neutrophil-lymphocyte ratio (NLR), were used to analyze and correlate with systemic inflammation and immunosuppression. Immunohistochemistry was performed to evaluate PD-L1 expression. RESULTS: Membranous PD-L1 expression was identified in 31% (98/313) of newly diagnosed and 46% (18/39) of matched recurrent tumors. TIL were found in 26% (82/313) of primary tumors and both density and location were found to be significantly associated with PD-L1 expression (p < 0.001). Interestingly, PD-L1 expressing tumors had more frequently areas with sarcomatous differentiation (p < 0.001) and were significantly associated with lower lymphocyte count (p = 0.018) and higher NLR ratio (p = 0.004) upon diagnosis. Importantly, PD-L1 expression was an independent poor prognostic marker in our cohort. CONCLUSION: Taken together, our 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.
PURPOSE: Glioblastoma is the most common primary malignant brain tumor in the adult, whose grim prognosis largely relates to the absence of effective treatment targets. Given its success in other cancers, immunotherapy has been trialed in glioblastoma and failed to demonstrate the expected benefit. Importantly, these disappointing results highlight the importance of understanding the unique and transforming biology of glioblastoma and its microenvironment. Our goal was to evaluate and characterize the expression of PD-L1 through immunohistochemistry in a large glioblastoma cohort. We further studied PD-L1 expression-associated prognosis and its correlation to systemic and neuropathological parameters. METHODS: A series of 352 glioblastoma specimens (313 initial resection, 39 matched recurrences) was collected, with a detailed characterization of tumor neuropathological characteristics, including the presence, density and location of tumor infiltrating lymphocytes (TIL). Two hematological markers, absolute lymphocyte count and neutrophil-lymphocyte ratio (NLR), were used to analyze and correlate with systemic inflammation and immunosuppression. Immunohistochemistry was performed to evaluate PD-L1 expression. RESULTS: Membranous PD-L1 expression was identified in 31% (98/313) of newly diagnosed and 46% (18/39) of matched recurrent tumors. TIL were found in 26% (82/313) of primary tumors and both density and location were found to be significantly associated with PD-L1 expression (p < 0.001). Interestingly, PD-L1 expressing tumors had more frequently areas with sarcomatous differentiation (p < 0.001) and were significantly associated with lower lymphocyte count (p = 0.018) and higher NLR ratio (p = 0.004) upon diagnosis. Importantly, PD-L1 expression was an independent poor prognostic marker in our cohort. CONCLUSION: Taken together, our 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.
Authors: Patrick Y Wen; Michael Weller; Eudocia Quant Lee; Brian M Alexander; Jill S Barnholtz-Sloan; Floris P Barthel; Tracy T Batchelor; Ranjit S Bindra; Susan M Chang; E Antonio Chiocca; Timothy F Cloughesy; John F DeGroot; Evanthia Galanis; Mark R Gilbert; Monika E Hegi; Craig Horbinski; Raymond Y Huang; Andrew B Lassman; Emilie Le Rhun; Michael Lim; Minesh P Mehta; Ingo K Mellinghoff; Giuseppe Minniti; David Nathanson; Michael Platten; Matthias Preusser; Patrick Roth; Marc Sanson; David Schiff; Susan C Short; Martin J B Taphoorn; Joerg-Christian Tonn; Jonathan Tsang; Roel G W Verhaak; Andreas von Deimling; Wolfgang Wick; Gelareh Zadeh; David A Reardon; Kenneth D Aldape; Martin J van den Bent Journal: Neuro Oncol Date: 2020-08-17 Impact factor: 12.300
Authors: Karolina Woroniecka; Pakawat Chongsathidkiet; Kristen Rhodin; Hanna Kemeny; Cosette Dechant; S Harrison Farber; Aladine A Elsamadicy; Xiuyu Cui; Shohei Koyama; Christina Jackson; Landon J Hansen; Tanner M Johanns; Luis Sanchez-Perez; Vidyalakshmi Chandramohan; Yen-Rei Andrea Yu; Darell D Bigner; Amber Giles; Patrick Healy; Glenn Dranoff; Kent J Weinhold; Gavin P Dunn; Peter E Fecci Journal: Clin Cancer Res Date: 2018-02-07 Impact factor: 12.531
Authors: Gavin P Dunn; Mikael L Rinne; Jill Wykosky; Giannicola Genovese; Steven N Quayle; Ian F Dunn; Pankaj K Agarwalla; Milan G Chheda; Benito Campos; Alan Wang; Cameron Brennan; Keith L Ligon; Frank Furnari; Webster K Cavenee; Ronald A Depinho; Lynda Chin; William C Hahn Journal: Genes Dev Date: 2012-04-15 Impact factor: 11.361
Authors: Pakawat Chongsathidkiet; Christina Jackson; Shohei Koyama; Franziska Loebel; Xiuyu Cui; S Harrison Farber; Karolina Woroniecka; Aladine A Elsamadicy; Cosette A Dechant; Hanna R Kemeny; Luis Sanchez-Perez; Tooba A Cheema; Nicholas C Souders; James E Herndon; Jean-Valery Coumans; Jeffrey I Everitt; Brian V Nahed; John H Sampson; Michael D Gunn; Robert L Martuza; Glenn Dranoff; William T Curry; Peter E Fecci Journal: Nat Med Date: 2018-08-13 Impact factor: 53.440