PD-L1 expression in medulloblastoma: An evaluation by subgroup

Allison M. Martin, Christopher J. Nirschl, Magda J. Polanczyk, W. Robert Bell, Thomas R. Nirschl, Sarah Harris-Bookman, Jillian Phallen, Jessica Hicks, Daniel Martinez, Aleksandra Ogurtsova, Haiying Xu, Lisa M. Sullivan, Alan K. Meeker, Eric H. Raabe, Kenneth J. Cohen, Charles G. Eberhart, Peter C. Burger, Mariarita Santi, Janis M. Taube, Drew M. PardollCharles G. Drake, Michael Lim

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-γ robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-γ), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

Original languageEnglish (US)
Pages (from-to)19177-19191
Number of pages15
JournalOncotarget
Volume9
Issue number27
DOIs
StatePublished - Apr 10 2018
Externally publishedYes

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Medulloblastoma
Interferon-gamma
Biomarkers
Cell Line
Tumor Microenvironment
Gamma Rays
Brain Neoplasms
Neoplasms
Radiation
Pediatrics
Cytokines

Keywords

  • B7-H1
  • Brain tumor
  • Medulloblastoma
  • PD-1
  • PD-L1

ASJC Scopus subject areas

  • Oncology

Cite this

Martin, A. M., Nirschl, C. J., Polanczyk, M. J., Bell, W. R., Nirschl, T. R., Harris-Bookman, S., ... Lim, M. (2018). PD-L1 expression in medulloblastoma: An evaluation by subgroup. Oncotarget, 9(27), 19177-19191. https://doi.org/10.18632/oncotarget.24951

PD-L1 expression in medulloblastoma : An evaluation by subgroup. / Martin, Allison M.; Nirschl, Christopher J.; Polanczyk, Magda J.; Bell, W. Robert; Nirschl, Thomas R.; Harris-Bookman, Sarah; Phallen, Jillian; Hicks, Jessica; Martinez, Daniel; Ogurtsova, Aleksandra; Xu, Haiying; Sullivan, Lisa M.; Meeker, Alan K.; Raabe, Eric H.; Cohen, Kenneth J.; Eberhart, Charles G.; Burger, Peter C.; Santi, Mariarita; Taube, Janis M.; Pardoll, Drew M.; Drake, Charles G.; Lim, Michael.

In: Oncotarget, Vol. 9, No. 27, 10.04.2018, p. 19177-19191.

Research output: Contribution to journalArticle

Martin, AM, Nirschl, CJ, Polanczyk, MJ, Bell, WR, Nirschl, TR, Harris-Bookman, S, Phallen, J, Hicks, J, Martinez, D, Ogurtsova, A, Xu, H, Sullivan, LM, Meeker, AK, Raabe, EH, Cohen, KJ, Eberhart, CG, Burger, PC, Santi, M, Taube, JM, Pardoll, DM, Drake, CG & Lim, M 2018, 'PD-L1 expression in medulloblastoma: An evaluation by subgroup', Oncotarget, vol. 9, no. 27, pp. 19177-19191. https://doi.org/10.18632/oncotarget.24951
Martin AM, Nirschl CJ, Polanczyk MJ, Bell WR, Nirschl TR, Harris-Bookman S et al. PD-L1 expression in medulloblastoma: An evaluation by subgroup. Oncotarget. 2018 Apr 10;9(27):19177-19191. https://doi.org/10.18632/oncotarget.24951
Martin, Allison M. ; Nirschl, Christopher J. ; Polanczyk, Magda J. ; Bell, W. Robert ; Nirschl, Thomas R. ; Harris-Bookman, Sarah ; Phallen, Jillian ; Hicks, Jessica ; Martinez, Daniel ; Ogurtsova, Aleksandra ; Xu, Haiying ; Sullivan, Lisa M. ; Meeker, Alan K. ; Raabe, Eric H. ; Cohen, Kenneth J. ; Eberhart, Charles G. ; Burger, Peter C. ; Santi, Mariarita ; Taube, Janis M. ; Pardoll, Drew M. ; Drake, Charles G. ; Lim, Michael. / PD-L1 expression in medulloblastoma : An evaluation by subgroup. In: Oncotarget. 2018 ; Vol. 9, No. 27. pp. 19177-19191.
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AU - Nirschl, Christopher J.

AU - Polanczyk, Magda J.

AU - Bell, W. Robert

AU - Nirschl, Thomas R.

AU - Harris-Bookman, Sarah

AU - Phallen, Jillian

AU - Hicks, Jessica

AU - Martinez, Daniel

AU - Ogurtsova, Aleksandra

AU - Xu, Haiying

AU - Sullivan, Lisa M.

AU - Meeker, Alan K.

AU - Raabe, Eric H.

AU - Cohen, Kenneth J.

AU - Eberhart, Charles G.

AU - Burger, Peter C.

AU - Santi, Mariarita

AU - Taube, Janis M.

AU - Pardoll, Drew M.

AU - Drake, Charles G.

AU - Lim, Michael

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N2 - Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-γ robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-γ), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor.

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