University of Oulu

Väyrynen, S., Zhang, J., Yuan, C., Väyrynen, J., Dias Costa, A., Williams, H., Morales-Oyarvide, V., Lau, M., Rubinson, D., Dunne, R., Kozak, M., Wang, W., Agostini-Vulaj, D., Drage, M., Brais, L., Reilly, E., Rahma, O., Clancy, T., Wang, J., Linehan, D., Aguirre, A., Fuchs, C., Coussens, L., Chang, D., Koong, A., Hezel, A., Ogino, S., Nowak, J., Wolpin, B. (2020) Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer. Clinical Cancer Research, 27 (4), 1069-1081. https://doi.org/10.1158/1078-0432.CCR-20-3141

Composition, spatial characteristics, and prognostic significance of myeloid cell infiltration in pancreatic cancer

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Author: Väyrynen, Sara A.1; Zhang, Jinming1; Yuan, Chen1;
Organizations: 1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
3Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
4Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
5Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA
6Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
7Department of Medicine, Brigham and Women´s Hospital and Harvard Medical School, Boston, MA
8Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
9Department of General Surgery, University of Rochester Medical Center, Rochester, NY
10Broad Institute of MIT and Harvard, Cambridge, MA
11Department of Medical Oncology, Yale Cancer Center, New Haven, Connecticut
12Department of Medicine, Yale School of Medicine, New Haven, Connecticut
13Department of Medical Oncology, Smilow Cancer Hospital, New Haven, Connecticut
14Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR
15Knight Cancer Research Institute, Oregon Health and Science University, Portland, OR
16Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
17Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
18Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA
19Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2021042611923
Language: English
Published: American Association for Cancer Research, 2021
Publish Date: 2021-12-01
Description:

Abstract

Purpose: 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.

Experimental Design: 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.

Results: 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.

Conclusions: 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.

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Series: Clinical cancer research
ISSN: 1078-0432
ISSN-E: 1557-3265
ISSN-L: 1078-0432
Volume: 27
Issue: 4
Pages: 1069 - 1081
DOI: 10.1158/1078-0432.CCR-20-3141
OADOI: https://oadoi.org/10.1158/1078-0432.CCR-20-3141
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: S.A. Väyrynen was supported by the Finnish Cultural Foundation and Orion Research Foundation sr. S. Ogino was supported in part by NIH grant R35 CA197735. B.M. Wolpin was supported by the Hale Family Center for Pancreatic Cancer Research, Lustgarten Foundation Dedicated Laboratory program, NIH grant U01 CA210171, NIH grant P50 CA127003, Stand Up to Cancer, Pancreatic Cancer Action Network, Noble Effort Fund, Wexler Family Fund, Promises for Purple and McCarthy Strong.
Copyright information: © 2020 American Association for Cancer Research.