PD-L1 expression in medulloblastoma: an evaluation by subgroup

Martin, Allison; Nirschl, Christopher J.; Polanczyk, Magda J.; Bell, William R.; Nirschl, Thomas R.; Harris-Bookman, Sarah; Phallen, Jillian; Hicks, Jessica L.; Martı́nez, Daniel; Ogurtsova, Aleksandra; Xu, Huimin; Sullivan, Lisa; 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

doi:10.18632/oncotarget.24951

Cited by 47 publications

(54 citation statements)

References 63 publications

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“…These findings are particularly significant for MB research as little is known about MB-derived exosomal packaging, production, or their contents. Exosomes are known to contribute to tumor progression, and possible initiation, by shuttling oncogenes and oncoproteins from tumor cells to local and distal cells [ 6 , 43 , 44 ]. The contents of cancer cell exosomes, and the molecules associated with B7-H3 in MB-derived exosomes, could provide valuable insight into how B7-H3-packaged exosomes contribute to MB progression.…”

Section: Discussionmentioning

confidence: 99%

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

Purvis

Velpula

Guda

et al. 2020

IJMS

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(1) Aim: Medulloblastoma is the most common aggressive pediatric cancer of the central nervous system. Improved therapies are necessary to improve life outcomes for medulloblastoma patients. Exosomes are a subset of extracellular vesicles that are excreted outside of the cell, and can transport nucleic acids and proteins from donor cells to nearby recipient cells of the same or dissimilar tissues. Few publications exist exploring the role that exosomes play in medulloblastoma pathogenesis. In this study, we found B7-H3, an immunosuppressive immune checkpoint, present in D283 cell-derived exosomes. (2) Methods: Utilizing mass spectrometry and immunoblotting, the presence of B7-H3 in D283 control and B7-H3 overexpressing exosomes was confirmed. Exosomes were isolated by Systems Biosciences from cultured cells as well as with an isolation kit that included ultracentrifugation steps. Overlay experiments were performed to determine mechanistic impact of exosomes on recipient cells by incubating isolated exosomes in serum-free media with target cells. Impact of D283 exosome incubation on endothelial and UW228 medulloblastoma cells was assessed by immunoblotting. Immunocytochemistry was employed to visualize exosome fusion with recipient cells. (3) Results: Overexpressing B7-H3 in D283 cells increases exosomal production and size distribution. Mass spectrometry revealed a host of novel, pathogenic molecules associated with B7-H3 in these exosomes including STAT3, CCL5, MMP9, and PI3K pathway molecules. Additionally, endothelial and UW228 cells incubated with D283-derived B7-H3-overexpressing exosomes induced B7-H3 expression while pSTAT1 levels decreased in UW228 cells. (4) Conclusions: In total, our results reveal a novel role in exosome production and packaging for B7-H3 that may contribute to medulloblastoma progression.

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Section: Discussionmentioning

confidence: 99%

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

Purvis

Velpula

Guda

et al. 2020

IJMS

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“…The PD1/PD-L1 axis has been investigated and is considered a promising target for immunotherapy in MBs ( 13 , 14 , 21 ). The present study investigated PD-L1 expression in the patient cohort; however, no positive staining was observed ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Vermeulen et al (13) reported no programmed cell death protein ligand 1 (PD-L1) expression in 26 MB cohorts, suggesting limited or no added value for immunotherapy with PD1/PD-L1 blockers in MB. Conversely, Martin et al (14) demonstrated that PD-L1 is expressed at low levels in MB to facilitate immune escape.…”

Section: Introductionmentioning

confidence: 99%

Immune cell infiltration and cytokine secretion analysis reveal a non-inflammatory microenvironment of medulloblastoma

Diao

Zhang

et al. 2020

Oncol Lett

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Medulloblastoma (MB) is the most common lethal malignant pediatric brain tumor. Adjuvant immunotherapy for medulloblastoma has been proposed in both pre-clinical and clinical practice. To provide a precision strategy of designing immunotherapy for MB, the present study performed a descriptive analysis of immune microenvironment in a cohort and compared the differences between four subgroups of MB. Subtypes (WNT, SHH Group 3 and Group 4) of medulloblastoma were identified using K-means clustering according to the expression of signature genes. Tumor infiltrating immune cell population was assessed by both bio-informative algorithm based on gene expression and immunohistochemistry staining. Cytokines in tumor microenvironment were detected using Luminex. Gene Set Enrichment Analysis demonstrated a raised immune response in the SHH subgroup. Lymphocyte infiltration was low in all four subgroups, while more CD4 + T cells were observed in the Group 4 subtype. Programmed cell death protein 1 (PD1)/ ligand 1 (PD-L1) expression was absent in the cohort. The SHH subtype recruited more activated tumor associated macrophage/microglia compared with the other subgroups. Cytokines within the MB microenvironment were low compared with the glioblastoma samples. In contrast to glioblastoma, the immune microenvironment of pediatric MB is non-inflammatory and does not recruit many immune cells. These observations provide important considerations for the design of immunotherapeutic approaches for MB, such as inducing more lymphocytes into the tumor microenvironment.

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“…While certain studies documented limited levels of PD-L1 in medulloblastoma, one study showed that the SHH variant has higher PD-L1 expression than the other groups (and lowest MYC expression). 91 Groups 3 and 4 had the highest levels of MYC expression (and lowest PD-L1 expression). This study subsequently showed in vitro IFN-y-induced expression of PD-L1 in all cell lines while radiation stimulated variable expression.…”

Section: Checkpoint Inhibitors In Medulloblastomamentioning

confidence: 95%

<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

Kabir¹,

Kunos²,

Villanó³

et al. 2020

ITT

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Background: Immune-mediated therapies have transformed the treatment of metastatic melanoma and renal, bladder, and both small and non-small cell lung carcinomas. However, immunotherapy is yet to demonstrate dramatic results in brain tumors like medulloblastoma for a variety of reasons. Recent pre-clinical and early phase human trials provide encouraging results that may overcome the challenges of central nervous system (CNS) tumors, which include the intrinsic immunosuppressive properties of these cancers, a lack of antigen targets, antigenic variability, and the immune-restrictive site of the CNS. These studies highlight the growing potential of immunotherapy to treat patients with medulloblastoma, a disease that is a frequent cause of morbidity and mortality to children and young adults. Methods: We conducted an inclusive review of the PubMed-indexed literature and studies listed in clinicaltrials.gov using combinations of the keywords medulloblastoma, immunotherapy, CNS tumors, brain tumors, vaccines, oncolytic virus, natural killer, and CAR T to identify trials evaluating immunotherapy in preclinical experiments or in patients with medulloblastoma. Given a limited number of investigations using immunotherapy to treat patients with medulloblastoma, 24 studies were selected for final analysis and manuscript citation. Results: This review presents results from pre-clinical studies in medulloblastoma cell lines, animal models, and the limited trials involving human patients. Conclusion: From our review, we suggest that cancer vaccines, oncolytic viral therapy, natural killer cells, and CAR T therapy hold promise against the innate immunosuppressive properties of medulloblastoma in order to prolong survival. There is an unmet need for immunotherapy regimens that target overexpressed antigens in medulloblastoma tumors. We advocate for more combination treatment clinical trials using conventional surgical and radiochemotherapy approaches in the near-term clinical development.

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PD-L1 expression in medulloblastoma: an evaluation by subgroup

Cited by 47 publications

References 63 publications

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role

Immune cell infiltration and cytokine secretion analysis reveal a non-inflammatory microenvironment of medulloblastoma

<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

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