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Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence

BACKGROUND: The tumor microenvironment (TME) is a complex mixture of tumor epithelium, stroma and immune cells, and the immune component of the TME is highly prognostic for tumor progression and patient outcome. In lung cancer, anti-PD-1 therapy significantly improves patient survival through activa...

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Autores principales: Enfield, Katey S. S., Martin, Spencer D., Marshall, Erin A., Kung, Sonia H. Y., Gallagher, Paul, Milne, Katy, Chen, Zhaoyang, Nelson, Brad H., Lam, Stephen, English, John C., MacAulay, Calum E., Lam, Wan L., Guillaud, Martial
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335759/
https://www.ncbi.nlm.nih.gov/pubmed/30651131
http://dx.doi.org/10.1186/s40425-018-0488-6
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author Enfield, Katey S. S.
Martin, Spencer D.
Marshall, Erin A.
Kung, Sonia H. Y.
Gallagher, Paul
Milne, Katy
Chen, Zhaoyang
Nelson, Brad H.
Lam, Stephen
English, John C.
MacAulay, Calum E.
Lam, Wan L.
Guillaud, Martial
author_facet Enfield, Katey S. S.
Martin, Spencer D.
Marshall, Erin A.
Kung, Sonia H. Y.
Gallagher, Paul
Milne, Katy
Chen, Zhaoyang
Nelson, Brad H.
Lam, Stephen
English, John C.
MacAulay, Calum E.
Lam, Wan L.
Guillaud, Martial
author_sort Enfield, Katey S. S.
collection PubMed
description BACKGROUND: The tumor microenvironment (TME) is a complex mixture of tumor epithelium, stroma and immune cells, and the immune component of the TME is highly prognostic for tumor progression and patient outcome. In lung cancer, anti-PD-1 therapy significantly improves patient survival through activation of T cell cytotoxicity against tumor cells. Direct contact between CD8+ T cells and target cells is necessary for CD8+ T cell activity, indicating that spatial organization of immune cells within the TME reflects a critical process in anti-tumor immunity. Current immunohistochemistry (IHC) imaging techniques identify immune cell numbers and densities, but lack assessment of cell–cell spatial relationships (or “cell sociology”). Immune functionality, however, is often dictated by cell-to-cell contact and cannot be resolved by simple metrics of cell density (for example, number of cells per mm(2)). To address this issue, we developed a Hyperspectral Cell Sociology technology platform for the analysis of cell–cell interactions in multi-channel IHC-stained tissue. METHODS: Tissue sections of primary tumors from lung adenocarcinoma patients with known clinical outcome were stained using multiplex IHC for CD3, CD8, and CD79a, and hyperspectral image analysis determined the phenotype of all cells. A Voronoi diagram for each cell was used to approximate cell boundaries, and the cell type of all neighboring cells was identified and quantified. Monte Carlo analysis was used to assess whether cell sociology patterns were likely due to random distributions of the cells. RESULTS: High density of intra-tumoral CD8+ T cells was significantly associated with non-recurrence of tumors. A cell sociology pattern of CD8+ T cells surrounded by tumor cells was more significantly associated with non-recurrence compared to CD8+ T cell density alone. CD3+ CD8- T cells surrounded by tumor cells was also associated with non-recurrence, but at a similar significance as cell density alone. Cell sociology metrics improved recurrence classifications of 12 patients. Monte Carlo re-sampling analysis determined that these cell sociology patterns were non-random. CONCLUSION: Hyperspectral Cell Sociology expands our understanding of the complex interplay between tumor cells and immune infiltrate. This technology could improve predictions of responses to immunotherapy and lead to a deeper understanding of anti-tumor immunity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-018-0488-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-63357592019-01-23 Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence Enfield, Katey S. S. Martin, Spencer D. Marshall, Erin A. Kung, Sonia H. Y. Gallagher, Paul Milne, Katy Chen, Zhaoyang Nelson, Brad H. Lam, Stephen English, John C. MacAulay, Calum E. Lam, Wan L. Guillaud, Martial J Immunother Cancer Research Article BACKGROUND: The tumor microenvironment (TME) is a complex mixture of tumor epithelium, stroma and immune cells, and the immune component of the TME is highly prognostic for tumor progression and patient outcome. In lung cancer, anti-PD-1 therapy significantly improves patient survival through activation of T cell cytotoxicity against tumor cells. Direct contact between CD8+ T cells and target cells is necessary for CD8+ T cell activity, indicating that spatial organization of immune cells within the TME reflects a critical process in anti-tumor immunity. Current immunohistochemistry (IHC) imaging techniques identify immune cell numbers and densities, but lack assessment of cell–cell spatial relationships (or “cell sociology”). Immune functionality, however, is often dictated by cell-to-cell contact and cannot be resolved by simple metrics of cell density (for example, number of cells per mm(2)). To address this issue, we developed a Hyperspectral Cell Sociology technology platform for the analysis of cell–cell interactions in multi-channel IHC-stained tissue. METHODS: Tissue sections of primary tumors from lung adenocarcinoma patients with known clinical outcome were stained using multiplex IHC for CD3, CD8, and CD79a, and hyperspectral image analysis determined the phenotype of all cells. A Voronoi diagram for each cell was used to approximate cell boundaries, and the cell type of all neighboring cells was identified and quantified. Monte Carlo analysis was used to assess whether cell sociology patterns were likely due to random distributions of the cells. RESULTS: High density of intra-tumoral CD8+ T cells was significantly associated with non-recurrence of tumors. A cell sociology pattern of CD8+ T cells surrounded by tumor cells was more significantly associated with non-recurrence compared to CD8+ T cell density alone. CD3+ CD8- T cells surrounded by tumor cells was also associated with non-recurrence, but at a similar significance as cell density alone. Cell sociology metrics improved recurrence classifications of 12 patients. Monte Carlo re-sampling analysis determined that these cell sociology patterns were non-random. CONCLUSION: Hyperspectral Cell Sociology expands our understanding of the complex interplay between tumor cells and immune infiltrate. This technology could improve predictions of responses to immunotherapy and lead to a deeper understanding of anti-tumor immunity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-018-0488-6) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-16 /pmc/articles/PMC6335759/ /pubmed/30651131 http://dx.doi.org/10.1186/s40425-018-0488-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Enfield, Katey S. S.
Martin, Spencer D.
Marshall, Erin A.
Kung, Sonia H. Y.
Gallagher, Paul
Milne, Katy
Chen, Zhaoyang
Nelson, Brad H.
Lam, Stephen
English, John C.
MacAulay, Calum E.
Lam, Wan L.
Guillaud, Martial
Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
title Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
title_full Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
title_fullStr Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
title_full_unstemmed Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
title_short Hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
title_sort hyperspectral cell sociology reveals spatial tumor-immune cell interactions associated with lung cancer recurrence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335759/
https://www.ncbi.nlm.nih.gov/pubmed/30651131
http://dx.doi.org/10.1186/s40425-018-0488-6
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