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IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT
PURPOSE: To clarify the immunoreactivity and potential immunotherapeutic targets of pediatric low- and high-grade gliomas (HGG). METHODS: Spatial sequential immunofluorescence (seqIFTM) of 24 protein markers, NanoString analysis of 770 immune genes, and scRNA sequencing were used to profile and char...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260064/ http://dx.doi.org/10.1093/neuonc/noad073.197 |
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author | Najem, Hinda Tripathi, Shashwat McCortney, Kathleen Horak, Victoria Jane Leonard, Kaethe Steffens, Alicia Walshon, Jordain Horbinski, Craig M Wadhwani, Nitin R James, Charles David Lam, Sandi Lesniak, Maciej S Burks, Jared K Heimberger, Amy B DeCuypere, Michael G |
author_facet | Najem, Hinda Tripathi, Shashwat McCortney, Kathleen Horak, Victoria Jane Leonard, Kaethe Steffens, Alicia Walshon, Jordain Horbinski, Craig M Wadhwani, Nitin R James, Charles David Lam, Sandi Lesniak, Maciej S Burks, Jared K Heimberger, Amy B DeCuypere, Michael G |
author_sort | Najem, Hinda |
collection | PubMed |
description | PURPOSE: To clarify the immunoreactivity and potential immunotherapeutic targets of pediatric low- and high-grade gliomas (HGG). METHODS: Spatial sequential immunofluorescence (seqIFTM) of 24 protein markers, NanoString analysis of 770 immune genes, and scRNA sequencing were used to profile and characterize the tumor microenvironment (TME) of 13 newly diagnosed WHO grade 1 pilocytic astrocytomas (PA), 6 pediatric HGG, and 3 normal brain (NB) samples. RESULTS: Relative to NB, HGGs were enriched with T cells, cancer-associated fibroblasts (CAF), CD11c+ antigen-presenting cells, and CD163+ macrophages. In contrast, PA showed more CD11c+P2RY12+ microglia and CD11c+CD205+ dendritic cells (DCs). TMEM119+ microglia were present in NB and brain adjacent to PA but were rare within the TME of all gliomas regardless of histology. PA uniquely contained naïve CD45RO-FoxP3-PD-1-TIM-3-LAG-3- T cells forming immunological synapses, as visualized by Lck+ expression at the membrane interfaces, during interaction with either microglia or DCs. This finding was not encountered in HGG. TIM-3 was the most frequently expressed immune modulatory target on all the myeloid populations, regardless of tumor histology. PD-L1 expression, especially on microglia, was more frequent in PA than in HGG. NanoString analysis revealed the pro-inflammatory and enabler of diapedesis IL-1 pathway genes (IL1RAP, TICAM2, and IRAK4) were upregulated in PA relative to the matched adjacent brain using unsupervised hierarchical clustering. CONCLUSIONS: Based on multiple orthogonal analysis strategies, PAs display a more pro-inflammatory phenotype, in comparison to HGG, suggesting immunological surveillance that may be driven by IL-1, as a baseline feature at presentation. |
format | Online Article Text |
id | pubmed-10260064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102600642023-06-13 IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT Najem, Hinda Tripathi, Shashwat McCortney, Kathleen Horak, Victoria Jane Leonard, Kaethe Steffens, Alicia Walshon, Jordain Horbinski, Craig M Wadhwani, Nitin R James, Charles David Lam, Sandi Lesniak, Maciej S Burks, Jared K Heimberger, Amy B DeCuypere, Michael G Neuro Oncol Final Category: Immunology/Immunotherapy - IMMU PURPOSE: To clarify the immunoreactivity and potential immunotherapeutic targets of pediatric low- and high-grade gliomas (HGG). METHODS: Spatial sequential immunofluorescence (seqIFTM) of 24 protein markers, NanoString analysis of 770 immune genes, and scRNA sequencing were used to profile and characterize the tumor microenvironment (TME) of 13 newly diagnosed WHO grade 1 pilocytic astrocytomas (PA), 6 pediatric HGG, and 3 normal brain (NB) samples. RESULTS: Relative to NB, HGGs were enriched with T cells, cancer-associated fibroblasts (CAF), CD11c+ antigen-presenting cells, and CD163+ macrophages. In contrast, PA showed more CD11c+P2RY12+ microglia and CD11c+CD205+ dendritic cells (DCs). TMEM119+ microglia were present in NB and brain adjacent to PA but were rare within the TME of all gliomas regardless of histology. PA uniquely contained naïve CD45RO-FoxP3-PD-1-TIM-3-LAG-3- T cells forming immunological synapses, as visualized by Lck+ expression at the membrane interfaces, during interaction with either microglia or DCs. This finding was not encountered in HGG. TIM-3 was the most frequently expressed immune modulatory target on all the myeloid populations, regardless of tumor histology. PD-L1 expression, especially on microglia, was more frequent in PA than in HGG. NanoString analysis revealed the pro-inflammatory and enabler of diapedesis IL-1 pathway genes (IL1RAP, TICAM2, and IRAK4) were upregulated in PA relative to the matched adjacent brain using unsupervised hierarchical clustering. CONCLUSIONS: Based on multiple orthogonal analysis strategies, PAs display a more pro-inflammatory phenotype, in comparison to HGG, suggesting immunological surveillance that may be driven by IL-1, as a baseline feature at presentation. Oxford University Press 2023-06-12 /pmc/articles/PMC10260064/ http://dx.doi.org/10.1093/neuonc/noad073.197 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Final Category: Immunology/Immunotherapy - IMMU Najem, Hinda Tripathi, Shashwat McCortney, Kathleen Horak, Victoria Jane Leonard, Kaethe Steffens, Alicia Walshon, Jordain Horbinski, Craig M Wadhwani, Nitin R James, Charles David Lam, Sandi Lesniak, Maciej S Burks, Jared K Heimberger, Amy B DeCuypere, Michael G IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT |
title | IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT |
title_full | IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT |
title_fullStr | IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT |
title_full_unstemmed | IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT |
title_short | IMMU-10. PILOCYTIC ASTROCYTOMAS SHOW EVIDENCE OF INTRINSIC IMMUNE SURVEILLANCE AND ACTIVATION WITHIN THE TUMOR MICROENVIRONMENT |
title_sort | immu-10. pilocytic astrocytomas show evidence of intrinsic immune surveillance and activation within the tumor microenvironment |
topic | Final Category: Immunology/Immunotherapy - IMMU |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260064/ http://dx.doi.org/10.1093/neuonc/noad073.197 |
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