TY - JOUR
T1 - Composition, Spatial Characteristics, and Prognostic Significance of Myeloid Cell Infiltration in Pancreatic Cancer
AU - Vayrynen, Sara A.
AU - Zhang, Jinming
AU - Yuan, Chen
AU - Vayrynen, Juha P.
AU - Costa, Andressa Dias
AU - Williams, Hannah
AU - Morales-Oyarvide, Vicente
AU - Lau, Mai Chan
AU - Rubinson, Douglas A.
AU - Dunne, Richard F.
AU - Kozak, Margaret M.
AU - Wang, Wenjia
AU - Agostini-Vulaj, Diana
AU - Drage, Michael G.
AU - Brais, Lauren
AU - Reilly, Emma
AU - Rahma, Osama
AU - Clancy, Thomas
AU - Wang, Jiping
AU - Linehan, David C.
AU - Aguirre, Andrew J.
AU - Fuchs, Charles S.
AU - Coussens, Lisa M.
AU - Chang, Daniel T.
AU - Koong, Albert C.
AU - Hezel, Aram F.
AU - Ogino, Shuji
AU - Nowak, Jonathan A.
AU - Wolpin, Brian M.
N1 - Funding Information:
S.A. V€ayrynen 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.
Funding Information:
S.A. V€ayrynen reports grants from Finnish Cultural Foundation and Orion Research Foundation sr during the conduct of the study. D.A. Rubinson reports personal fees from Boston Scientific outside the submitted work. R.F. Dunne reports personal fees from Exelixis Inc. outside the submitted work. O. Rahma reports personal fees from Imvax, GSK, Bayer, Genentech, Sobi, Puretech, Maverick Therapeutics, Five Prime, and Merck outside the submitted work; in addition, O. Rahma has a patent for Methods of using pembrolizumab and trebananib pending. A.J. Aguirre reports personal fees from Oncorus, Inc, Arrakis Therapeutics, and Merck outside the submitted work. C.S. Fuchs reports personal fees from Agios, Amylin Pharma, AstraZeneca, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, Evolveimmune Therapeutics, Genentech, Merck, Taiho, Unum Therapeutics, and Bain Capital outside the submitted work; serves as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; is a co-Founder of Evolveimmune Therapeutics and has equity in this private company; and had provided expert testimony for Amylin Pharmaceuticals and Eli Lilly. L.M. Coussens reports nonfinancial support from Cell Signaling Technologies, Syndax Pharmaceuticals Inc., and Deciphera Pharmaceuticals, LLC; personal fees from Syndax Pharmaceuticals, Inc, Carisma Therapeutics Inc, Verseau Therapeutics, Inc., Zymeworks, Inc., CytomX Therapeutics, Inc, Kineta Inc, (P30) Koch Institute for Integrated Cancer Research, Massachusetts Inst. of Tech., (P30) Salk Institute Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Dana-Farber Cancer Center Breast SPORE, (P30) Dana-Farber/Harvard Cancer Center, (P30) University of California, San Diego Moores Cancer Center, NIH/NCI-Frederick National Laboratory Advisory Committee (FNLAC), Cell Signaling Technologies, Susan G Komen Foundation, Komen Scholar, AbbVie Inc, and Shasqi, Inc.; other from Pharmacyclics, Inc [Steering committee for PCYC-1137-CA (NCT02436668)], Cancer Research Institute (CRI), The V Foundation for Cancer Research, Starr Cancer Consortium, Lustgarten Foundation for Pancreatic Cancer Research, Therapeutics Working Group, grants from Brenden-Colson Center for Pancreatic Health (PI: Coussens), NIH/NCI P30 CA069533 (PI: Druker), Syndax Pharmaceuticals Inc, Innate Pharma, Prospect Creek Foundation, Lustgarten Foundation for Pancreatic Cancer Research, NIH/NCI R01 CA226909 (PI: Varner/Cohen), NIH/NCI R01 CA223150 (PI: Jonas), NIH/NCI U01 CA224012 (mPI: Sears, Coussens, Demir, Brody), NIH/NHLBI R01 HL093056 (PI: Habecker), NIH/NICHD R21 HD099367 (PI: Maloyan), Johns Hopkins University (PI: Coussens), Oregon Health & Science University (SMMART), Cancer Research UK/OHSU Knight Cancer Institute CRUK6841219 (PI: Chang/Zhuang), NIH/NCI R01 CA169175 (PI: Schedin), and NIH/NCI T32 CA254888 (multiPI: Gray/ Coussens) outside the submitted work. A.C. Koong holds stock in Aravive, Inc and have served as a consultant for Aravive in the past. S. Ogino reports grants from NIH during the conduct of the study. B.M. Wolpin reports grants and personal fees from Celgene; grants from Eli Lilly; personal fees from BioLineRx and Grail outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
S.A. V€ayrynen 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
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/2/15
Y1 - 2021/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-20-3141
DO - 10.1158/1078-0432.CCR-20-3141
M3 - Article
AN - SCOPUS:85101164528
SN - 1078-0432
VL - 27
SP - 1069
EP - 1081
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -