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. Pardoll; Charles G. Drake; Michael Lim

doi:10.18632/oncotarget.24951

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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, T_H1 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 language	English (US)
Pages (from-to)	19177-19191
Number of pages	15
Journal	Oncotarget
Volume	9
Issue number	27
DOIs	https://doi.org/10.18632/oncotarget.24951
State	Published - Apr 10 2018

Bibliographical note

Funding Information:
Mr. Lee Blosser & Ms. Ada Tam for assistance in the Flow Cytometry Core; Esteban Velarde, Brian Francica, PhD & Sudipto Ganguly, PhD for assistance with the Irradiator Core; Helen Fedor, PhD for assistance in the Oncology Tissue Services Core; Duncan Stearns, MD for use of YM21 and UWM13; Lieping Chen, MD, PhD for use of 5H1 anti-CD274 human monoclonal antibody; Institute of Pathology at the University of Heidelberg for JHH MB Cohort Immunohistochemical Subgroup assignment.AMM: T32 Pediatric Hematology-Oncology (T32CA60441), Optimist Foundation, Giant Food Foundation; EHR: St. Baldrick's Foundation; ML: W.W. Smith Charitable Trust; This work was also supported by the NIH P30 CA006973 to the Johns Hopkins Sidney Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Publisher Copyright:
© Martin et al.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.18632/oncotarget.24951

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922386

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Martin, A. M., Nirschl, C. J., Polanczyk, M. J., Bell, W. R., Nirschl, T. R., Harris-Bookman, S., Phallen, J., Hicks, J., Martinez, D., Ogurtsova, A., Xu, H., Sullivan, L. M., Meeker, A. K., Raabe, E. H., Cohen, K. J., Eberhart, C. G., Burger, P. C., Santi, M., Taube, J. M., ... Lim, M. (2018). PD-L1 expression in medulloblastoma: An evaluation by subgroup. Oncotarget, 9(27), 19177-19191. https://doi.org/10.18632/oncotarget.24951

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

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title = "PD-L1 expression in medulloblastoma: An evaluation by subgroup",

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.",

keywords = "B7-H1, Brain tumor, Medulloblastoma, PD-1, PD-L1",

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

note = "Funding Information: Mr. Lee Blosser \& Ms. Ada Tam for assistance in the Flow Cytometry Core; Esteban Velarde, Brian Francica, PhD \& Sudipto Ganguly, PhD for assistance with the Irradiator Core; Helen Fedor, PhD for assistance in the Oncology Tissue Services Core; Duncan Stearns, MD for use of YM21 and UWM13; Lieping Chen, MD, PhD for use of 5H1 anti-CD274 human monoclonal antibody; Institute of Pathology at the University of Heidelberg for JHH MB Cohort Immunohistochemical Subgroup assignment.AMM: T32 Pediatric Hematology-Oncology (T32CA60441), Optimist Foundation, Giant Food Foundation; EHR: St. Baldrick's Foundation; ML: W.W. Smith Charitable Trust; This work was also supported by the NIH P30 CA006973 to the Johns Hopkins Sidney Kimmel Cancer Center and the Bloomberg\textasciitilde{}Kimmel Institute for Cancer Immunotherapy. Publisher Copyright: {\textcopyright} Martin et al.",

year = "2018",

month = apr,

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doi = "10.18632/oncotarget.24951",

language = "English (US)",

volume = "9",

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T1 - PD-L1 expression in medulloblastoma

T2 - An evaluation by subgroup

AU - Martin, Allison M.

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

N1 - Funding Information: Mr. Lee Blosser & Ms. Ada Tam for assistance in the Flow Cytometry Core; Esteban Velarde, Brian Francica, PhD & Sudipto Ganguly, PhD for assistance with the Irradiator Core; Helen Fedor, PhD for assistance in the Oncology Tissue Services Core; Duncan Stearns, MD for use of YM21 and UWM13; Lieping Chen, MD, PhD for use of 5H1 anti-CD274 human monoclonal antibody; Institute of Pathology at the University of Heidelberg for JHH MB Cohort Immunohistochemical Subgroup assignment.AMM: T32 Pediatric Hematology-Oncology (T32CA60441), Optimist Foundation, Giant Food Foundation; EHR: St. Baldrick's Foundation; ML: W.W. Smith Charitable Trust; This work was also supported by the NIH P30 CA006973 to the Johns Hopkins Sidney Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy. Publisher Copyright: © Martin et al.

PY - 2018/4/10

Y1 - 2018/4/10

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.

AB - 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.

KW - B7-H1

KW - Brain tumor

KW - Medulloblastoma

KW - PD-1

KW - PD-L1

UR - https://www.scopus.com/pages/publications/85045193706

UR - https://www.scopus.com/inward/citedby.url?scp=85045193706&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.24951

DO - 10.18632/oncotarget.24951

M3 - Article

C2 - 29721192

AN - SCOPUS:85045193706

SN - 1949-2553

VL - 9

SP - 19177

EP - 19191

JO - Oncotarget

JF - Oncotarget

IS - 27

ER -

PD-L1 expression in medulloblastoma: An evaluation by subgroup

Abstract

Bibliographical note

Keywords

UN SDGs

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