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

Sara A. Vayrynen, Jinming Zhang, Chen Yuan, Juha P. Vayrynen, 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. LinehanAndrew 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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 CD15þARG1þ 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.

Original languageEnglish (US)
Pages (from-to)1069-1081
Number of pages13
JournalClinical Cancer Research
Volume27
Issue number4
DOIs
StatePublished - Feb 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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