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PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma

  • Laboratory Investigation
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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.

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Funding

This work was funded by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by FCT—Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Ensino Superior under the project FCT/02/SAICT/2017/030625.

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Authors and Affiliations

  1. Neurosurgery Department, Hospital de Santo Antonio, Centro Hospitalar Universitario do Porto, Porto, Portugal

    Carolina Noronha & Joaquim Reis

  2. i3S- Institute for Investigation and Innovation in Health, Porto, Portugal

    Carolina Noronha, Ana Sofia Ribeiro, Fernando Schmitt & Joana Paredes

  3. Neuropathology Unit, Hospital de Santo Antonio, Centro Hospitalar Universitario do Porto, Porto, Portugal

    Ricardo Taipa

  4. Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal

    Ricardo Taipa

  5. Faculty of Medicine, University of Porto, Porto, Portugal

    Dina Leitão & Joana Paredes

  6. Anatomy Department, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal

    Joaquim Reis

  7. Neurosurgery Department, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, Lisboa, Portugal

    Cláudia Faria

  8. IMM - Instituto de Medicina Molecular João Lobo Antunes, Lisboa, Portugal

    Cláudia Faria

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  1. Carolina Noronha
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  2. Ana Sofia Ribeiro
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Contributions

Conceptualization: CN and JP; Methodology: CN, DL, RT, FS; Formal analysis and investigation: CN, ASR, RT, FS, JP; Writing—original draft preparation: CN; Writing—review and editing: CN, ASR, RT, JR, FS, CF, JP; Supervision: JP.

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Correspondence to Joana Paredes.

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The authors declare no conflict of interest.

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This study has been performed in accordance with the national regulative law for the handling of biological specimens from tumor banks, being the samples exclusively available for research purposes in retrospective studies, as well as under the international Helsinki declaration. Moreover, it has been also approved by the ethics committee at Centro Hospitalar Universitário do Porto (2017-104 (093-DEFI/091-CES).

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Noronha, C., Ribeiro, A.S., Taipa, R. et al. PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma. J Neurooncol 156, 453–464 (2022). https://doi.org/10.1007/s11060-021-03907-3

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