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Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma

BACKGROUND: The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurre...

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Autores principales: Ghatalia, Pooja, Gordetsky, Jennifer, Kuo, Fengshen, Dulaimi, Essel, Cai, Kathy Q., Devarajan, Karthik, Bae, Sejong, Naik, Gurudatta, Chan, Timothy A., Uzzo, Robert, Hakimi, A. Ari, Sonpavde, Guru, Plimack, Elizabeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540413/
https://www.ncbi.nlm.nih.gov/pubmed/31138299
http://dx.doi.org/10.1186/s40425-019-0621-1
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author Ghatalia, Pooja
Gordetsky, Jennifer
Kuo, Fengshen
Dulaimi, Essel
Cai, Kathy Q.
Devarajan, Karthik
Bae, Sejong
Naik, Gurudatta
Chan, Timothy A.
Uzzo, Robert
Hakimi, A. Ari
Sonpavde, Guru
Plimack, Elizabeth
author_facet Ghatalia, Pooja
Gordetsky, Jennifer
Kuo, Fengshen
Dulaimi, Essel
Cai, Kathy Q.
Devarajan, Karthik
Bae, Sejong
Naik, Gurudatta
Chan, Timothy A.
Uzzo, Robert
Hakimi, A. Ari
Sonpavde, Guru
Plimack, Elizabeth
author_sort Ghatalia, Pooja
collection PubMed
description BACKGROUND: The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurrence following surgery in localized ccRCC. METHODS: We morphologically identified and scored tumor infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) stained slides of patients with localized ccRCC (stage ≥T1b excluding stage IV). The University of Alabama at Birmingham (UAB) dataset (n = 159) was used to discover and the Fox Chase Cancer Center (FCCC) dataset (n = 198) was used to validate the results of morphologic immune cell analysis. We then performed gene expression analysis using the Immune Profile panel by NanoString in the UAB cohort and identified immune cells and pathways associated with recurrence, followed by validation in the Cancer Genome Atlas (TCGA) ccRCC dataset. Infiltrating immune cell types were identified by gene expression deconvolution. RESULTS: The presence of TILs identified by morphology correlated with higher T cell, Th1, CD8+ T and Treg gene signatures. Recurrence was associated with lower T cells and higher neutrophils. Higher Teffector (Teff)/Treg ratio correlated with lower rate of recurrence and was validated in the TCGA dataset. Genes associated with adaptive immune response were downregulated in tumors that recurred. Unsupervised hierarchical clustering identified a subset of patients with over-expression of adaptive response genes including CD8, CD3, GZMA/B, PRF1, IDO1, CTLA4, PDL1, ICOS and TIGIT. These patients had higher morphologic lymphocyte infiltration and T cell gene expression. Higher levels of TILs identified by morphology correlated with higher rates of recurrence in our discovery dataset but not in our validation set. CONCLUSIONS: Recurrence of ccRCC following surgery was associated with lower T cell infiltrate, lower adaptive immune response and higher neutrophil gene expression. Presence of higher Teff/Treg ratio correlated with lower recurrence. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0621-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-65404132019-06-03 Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma Ghatalia, Pooja Gordetsky, Jennifer Kuo, Fengshen Dulaimi, Essel Cai, Kathy Q. Devarajan, Karthik Bae, Sejong Naik, Gurudatta Chan, Timothy A. Uzzo, Robert Hakimi, A. Ari Sonpavde, Guru Plimack, Elizabeth J Immunother Cancer Research Article BACKGROUND: The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurrence following surgery in localized ccRCC. METHODS: We morphologically identified and scored tumor infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) stained slides of patients with localized ccRCC (stage ≥T1b excluding stage IV). The University of Alabama at Birmingham (UAB) dataset (n = 159) was used to discover and the Fox Chase Cancer Center (FCCC) dataset (n = 198) was used to validate the results of morphologic immune cell analysis. We then performed gene expression analysis using the Immune Profile panel by NanoString in the UAB cohort and identified immune cells and pathways associated with recurrence, followed by validation in the Cancer Genome Atlas (TCGA) ccRCC dataset. Infiltrating immune cell types were identified by gene expression deconvolution. RESULTS: The presence of TILs identified by morphology correlated with higher T cell, Th1, CD8+ T and Treg gene signatures. Recurrence was associated with lower T cells and higher neutrophils. Higher Teffector (Teff)/Treg ratio correlated with lower rate of recurrence and was validated in the TCGA dataset. Genes associated with adaptive immune response were downregulated in tumors that recurred. Unsupervised hierarchical clustering identified a subset of patients with over-expression of adaptive response genes including CD8, CD3, GZMA/B, PRF1, IDO1, CTLA4, PDL1, ICOS and TIGIT. These patients had higher morphologic lymphocyte infiltration and T cell gene expression. Higher levels of TILs identified by morphology correlated with higher rates of recurrence in our discovery dataset but not in our validation set. CONCLUSIONS: Recurrence of ccRCC following surgery was associated with lower T cell infiltrate, lower adaptive immune response and higher neutrophil gene expression. Presence of higher Teff/Treg ratio correlated with lower recurrence. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0621-1) contains supplementary material, which is available to authorized users. BioMed Central 2019-05-28 /pmc/articles/PMC6540413/ /pubmed/31138299 http://dx.doi.org/10.1186/s40425-019-0621-1 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
Ghatalia, Pooja
Gordetsky, Jennifer
Kuo, Fengshen
Dulaimi, Essel
Cai, Kathy Q.
Devarajan, Karthik
Bae, Sejong
Naik, Gurudatta
Chan, Timothy A.
Uzzo, Robert
Hakimi, A. Ari
Sonpavde, Guru
Plimack, Elizabeth
Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma
title Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma
title_full Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma
title_fullStr Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma
title_full_unstemmed Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma
title_short Prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma
title_sort prognostic impact of immune gene expression signature and tumor infiltrating immune cells in localized clear cell renal cell carcinoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540413/
https://www.ncbi.nlm.nih.gov/pubmed/31138299
http://dx.doi.org/10.1186/s40425-019-0621-1
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