Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors

Research output: Contribution to journalArticle

Arturas Ziemys, Michelle Kim, Alexander M. Menzies, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Larry Kwong, Ashley M. Holder, Genevieve Boland

Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify “hot” areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.

Original languageEnglish (US)
Article number757
JournalFrontiers in Oncology
Volume10
DOIs
StatePublished - May 14 2020

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Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors. / Ziemys, Arturas; Kim, Michelle; Menzies, Alexander M.; Wilmott, James S.; Long, Georgina V.; Scolyer, Richard A.; Kwong, Larry; Holder, Ashley M.; Boland, Genevieve.

In: Frontiers in Oncology, Vol. 10, 757, 14.05.2020.

Research output: Contribution to journalArticle

Harvard

Ziemys, A, Kim, M, Menzies, AM, Wilmott, JS, Long, GV, Scolyer, RA, Kwong, L, Holder, AM & Boland, G 2020, 'Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors' Frontiers in Oncology, vol. 10, 757. https://doi.org/10.3389/fonc.2020.00757

APA

Ziemys, A., Kim, M., Menzies, A. M., Wilmott, J. S., Long, G. V., Scolyer, R. A., ... Boland, G. (2020). Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors. Frontiers in Oncology, 10, [757]. https://doi.org/10.3389/fonc.2020.00757

Vancouver

Ziemys A, Kim M, Menzies AM, Wilmott JS, Long GV, Scolyer RA et al. Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors. Frontiers in Oncology. 2020 May 14;10. 757. https://doi.org/10.3389/fonc.2020.00757

Author

Ziemys, Arturas ; Kim, Michelle ; Menzies, Alexander M. ; Wilmott, James S. ; Long, Georgina V. ; Scolyer, Richard A. ; Kwong, Larry ; Holder, Ashley M. ; Boland, Genevieve. / Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors. In: Frontiers in Oncology. 2020 ; Vol. 10.

BibTeX

@article{20bb395060264ca6bc538d22bfacd152,
title = "Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors",
abstract = "Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify “hot” areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.",
keywords = "immune infiltrate, melanoma, RNAseq, spatial analysis, targeted therapy (TT)",
author = "Arturas Ziemys and Michelle Kim and Menzies, {Alexander M.} and Wilmott, {James S.} and Long, {Georgina V.} and Scolyer, {Richard A.} and Larry Kwong and Holder, {Ashley M.} and Genevieve Boland",
year = "2020",
month = "5",
day = "14",
doi = "10.3389/fonc.2020.00757",
language = "English (US)",
volume = "10",
journal = "Frontiers in Oncology",
issn = "2234-943X",
publisher = "Frontiers Media S. A.",

}

RIS

TY - JOUR

T1 - Integration of Digital Pathologic and Transcriptomic Analyses Connects Tumor-Infiltrating Lymphocyte Spatial Density With Clinical Response to BRAF Inhibitors

AU - Ziemys, Arturas

AU - Kim, Michelle

AU - Menzies, Alexander M.

AU - Wilmott, James S.

AU - Long, Georgina V.

AU - Scolyer, Richard A.

AU - Kwong, Larry

AU - Holder, Ashley M.

AU - Boland, Genevieve

PY - 2020/5/14

Y1 - 2020/5/14

N2 - Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify “hot” areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.

AB - Metastatic melanoma is one of the most immunogenic malignancies due to its high rate of mutations and neoantigen formation. Response to BRAF inhibitors (BRAFi) may be determined by intratumoral immune activation within melanoma metastases. To evaluate whether CD8+ T cell infiltration and distribution within melanoma metastases can predict clinical response to BRAFi, we developed a methodology to integrate immunohistochemistry with automated image analysis of CD8+ T cell position. CD8+ distribution patterns were correlated with gene expression data to identify and quantify “hot” areas within a tumor. Furthermore, the relative activation of CD8+cells, based on transcriptomic analysis, and their relationship to other CD8+ T cells and non-CD8+ cells within the tumor suggested a less crowded distribution of cells around activated CD8+ T cells. Furthermore, the relative activation of these CD8+ T cells was associated with improved clinical outcomes and decreased tumor cell proliferation. This study demonstrates the potential of digital pathomics to incorporate immune cell spatial distribution within metastases and RNAseq analysis to predict clinical response to BRAF inhibition in metastatic melanoma.

KW - immune infiltrate

KW - melanoma

KW - RNAseq

KW - spatial analysis

KW - targeted therapy (TT)

UR - http://www.scopus.com/inward/record.url?scp=85085493291&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85085493291&partnerID=8YFLogxK

U2 - 10.3389/fonc.2020.00757

DO - 10.3389/fonc.2020.00757

M3 - Article

VL - 10

JO - Frontiers in Oncology

T2 - Frontiers in Oncology

JF - Frontiers in Oncology

SN - 2234-943X

M1 - 757

ER -

ID: 64342906