Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer

Sara A Väyrynen; Jinming Zhang; Chen Yuan; Juha P Väyrynen; Andressa Dias Costa; Hannah Williams; Vicente Morales-Oyarvide; Mai Chan Lau; Douglas A Rubinson; Richard F Dunne; Margaret M Kozak; Wenjia Wang; Diana Agostini-Vulaj; Michael G Drage; Lauren Brais; Emma Reilly; Osama Rahma; Thomas Clancy; Jiping Wang; David C Linehan; Andrew J Aguirre; Charles S Fuchs; Lisa M Coussens; Daniel T Chang; Albert C Koong; Aram F Hezel; Shuji Ogino; Jonathan A Nowak; Brian M Wolpin

doi:10.1158/1078-0432.CCR-20-3141

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Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer

Journal article

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Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer

Sara A Väyrynen, Jinming Zhang, Chen Yuan, Juha P Väyrynen, Andressa Dias Costa, Hannah Williams, Vicente Morales-Oyarvide, Mai Chan Lau, Douglas A Rubinson, Richard F Dunne, …

Clinical cancer research, Vol.27(4), pp.1069-1081

02/15/2021

DOI: 10.1158/1078-0432.CCR-20-3141

PMCID: PMC8345232

PMID: 33262135

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https://doi.org/10.1158/1078-0432.CCR-20-3141View

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Abstract

Although abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress antitumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood. To generate spatially resolved tumor and immune cell data at single-cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, IFN regulatory factor 5, MRC1 (CD206)] in the PDAC tumor microenvironment. Spatial point pattern analyses were conducted to assess the degree of colocalization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes. In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, and differed by somatic genotype. High densities of CD15 ARG1 immunosuppressive granulocytic cells and M2-polarized macrophages were associated with worse patient survival. Moreover, beyond cell density, closer proximity of M2-polarized macrophages to tumor cells was strongly associated with disease-free survival, revealing the clinical significance and biologic importance of immune cell localization within tumor areas. A diverse set of myeloid cells are present within the PDAC tumor microenvironment and are distributed heterogeneously across patient tumors. Not only the densities but also the spatial locations of myeloid immune cells are associated with patient outcomes, highlighting the potential role of spatially resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy.

Aged

Carcinoma, Pancreatic Ductal - immunology

Carcinoma, Pancreatic Ductal - mortality

Carcinoma, Pancreatic Ductal - pathology

Carcinoma, Pancreatic Ductal - surgery

Cohort Studies

Disease-Free Survival

Female

Humans

Male

Middle Aged

Myeloid Cells - immunology

Neoplasm Recurrence, Local - epidemiology

Neoplasm Recurrence, Local - immunology

Neoplasm Recurrence, Local - prevention & control

Pancreas - immunology

Pancreas - pathology

Pancreas - surgery

Pancreatectomy

Pancreatic Neoplasms - immunology

Pancreatic Neoplasms - mortality

Pancreatic Neoplasms - pathology

Pancreatic Neoplasms - surgery

Prognosis

Retrospective Studies

Tumor Microenvironment - immunology

Details

Title: Subtitle: Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer
Creators: Sara A Väyrynen - Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
Jinming Zhang - Dana-Farber Cancer Institute
Chen Yuan - Dana-Farber Cancer Institute
Juha P Väyrynen - Dana-Farber Cancer Institute
Andressa Dias Costa - Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
Hannah Williams - Dana-Farber Cancer Institute
Vicente Morales-Oyarvide - Dana-Farber Cancer Institute
Mai Chan Lau - Brigham and Women's Hospital
Douglas A Rubinson - Dana-Farber Cancer Institute
Richard F Dunne - University of Rochester Medical Center
Margaret M Kozak - Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California.
Wenjia Wang - University of Rochester Medical Center
Diana Agostini-Vulaj - University of Rochester Medical Center
Michael G Drage - University of Rochester Medical Center
Lauren Brais - Dana-Farber Cancer Institute
Emma Reilly - Dana-Farber Cancer Institute
Osama Rahma - Dana-Farber Cancer Institute
Thomas Clancy - Brigham and Women's Hospital
Jiping Wang - Brigham and Women's Hospital
David C Linehan - University of Rochester Medical Center
Andrew J Aguirre - Broad Institute
Charles S Fuchs - Yale Cancer Center
Lisa M Coussens - Oregon Health & Science University
Daniel T Chang - Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California.
Albert C Koong - The University of Texas MD Anderson Cancer Center
Aram F Hezel - University of Rochester Medical Center
Shuji Ogino - Brigham and Women's Hospital
Jonathan A Nowak - Department of Pathology Brigham and Women's Hospital
Brian M Wolpin - Dana-Farber Cancer Institute
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.27(4), pp.1069-1081
DOI: 10.1158/1078-0432.CCR-20-3141
PMID: 33262135
PMCID: PMC8345232
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Grant note: P50 CA127003 / NCI NIH HHS U01 CA210171 / NCI NIH HHS K08 CA218420 / NCI NIH HHS U01 CA224146 / NCI NIH HHS R35 CA197735 / NCI NIH HHS
Language: English
Date published: 02/15/2021
Academic Unit: Radiation Oncology
Record Identifier: 9984313086102771

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