TY - JOUR
T1 - Leukocyte heterogeneity in pancreatic ductal adenocarcinoma
T2 - Phenotypic and spatial features associated with clinical outcome
AU - Liudahl, Shannon M.
AU - Betts, Courtney B.
AU - Sivagnanam, Shamilene
AU - Morales-Oyarvide, Vicente
AU - Silva, Annacarolina Da
AU - Yuan, Chen
AU - Hwang, Samuel
AU - Grossblatt-Wait, Alison
AU - Leis, Kenna R.
AU - Larson, William
AU - Lavoie, Meghan B.
AU - Robinson, Padraic
AU - Costa, Andressa Dias
AU - Väyrynen, Sara A.
AU - Clancy, Thomas E.
AU - Rubinson, Douglas A.
AU - Link, Jason
AU - Keith, Dove
AU - Horton, Wesley
AU - Tempero, Margaret A.
AU - Vonderheide, Robert H.
AU - Jaffee, Elizabeth M.
AU - Sheppard, Brett
AU - Goecks, Jeremy
AU - Sears, Rosalie C.
AU - Park, Byung S.
AU - Mori, Motomi
AU - Nowak, Jonathan A.
AU - Wolpin, Brian M.
AU - Coussens, Lisa M.
N1 - Funding Information:
We thank members of the Coussens and Wolpin-Nowak laboratories for critical feedback; Mr. Justin Tibbitts, Ms. Teresa Beechwood, and Dr. Jacklyn Woods for laboratory management; and Ms. Cathy Love for administrative assistance. We also thank the Parker Institute for Cancer Immunotherapy PRINCE trial translational team, the OHSU Histopathology Shared Resource, OHSU Surgical Pathology, the OHSU Cancer Registry, and the OHSU Knight Diagnostic Laboratories. We also thank all patients who donated tissue samples that made this study possible. The study and analyses were funded by a Stand Up To Cancer—Lustgarten Foundation Pancreatic Cancer Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT14-14) and the Brenden-Colson Center for Pancreatic Care at OHSU. Stand Up To Cancer is a division of the Entertainment Industry Foundation. The indicated grant is administered by the American Association for Cancer Research. L.M. Coussens acknowledges funding from the National Institutes of Health (1U01 CA224012, U2C CA233280, R01 CA223150, R01 CA226909, R21 HD099367), the Knight Cancer Institute, and the Brenden-Colson Center for Pancreatic Care at OHSU. Analytic methods used for image analysis at OHSU were developed and carried out with major support from the National Institutes of Health, National Cancer Institute Human Tumor Atlas Network (HTAN) Research Center (U2C CA233280), and the Prospect Creek Foundation to the OHSU SMMART (Serial Measurement of Molecular and Architectural Responses to Therapy) Program. B.M. Wolpin acknowledges funding from 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. S.A. Väyrynen is supported by the Finnish Cultural Foundation and Orion Research Foundation. R.H. Vonderheide receives research funding from Apexigen, Fibrogen, Inovio, Janssen, and Lilly. R.C. Sears acknowledges funding from the NIH (1U01 CA224012, U2C CA233280, U54 CA209988, R01 CA196228, and R01 CA186241) and the Brenden-Colson Center for Pancreatic Care at OHSU. This study was also made possible with support from the Oregon Clinical & Translational Research Institute (OCTRI), which is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR002369.
Funding Information:
S.A. Väyrynen reports grants from Finnish Cultural Foundation and grants from Orion Research Foundation during the conduct of the study. M.A. Tempero reports personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, grants from Celgene, personal
Funding Information:
fees from GlaxoSmithKline, grants from Halozyme, personal fees from ISPEN, personal fees from Karyopharm Therapeutics, personal fees from Merck & Co., personal fees from Seagen, and personal fees from Swedish Orphan Biovitrum outside the submitted work. R.H. Vonderheide reports having received consulting fees or honoraria from Celldex, Lilly, Medim-mune, and Verastem. R.H. Vonderheide is an inventor of a licensed patent relating to cancer cellular immunotherapy and receives royalties from Children’s Hospital Boston for a licensed research-only monoclonal antibody. E.M. Jaffee is a paid consultant for Adaptive Biotech, CSTONE, Achilles, DragonFly, and Genocea. E.M. Jaffee receives funding from Lustgarten Foundation and AduroBiotech and through a licensing agreement between AduroBiotech and JHU has the potential to receive royalties on GVAX. E.M. Jaffee is the chief medical advisor for Lustgarten and serves on the National Cancer Advisory Board and as an advisor to the Parker Institute for Cancer Immunotherapy (PICI). R.C. Sears reports grants from NIH during the conduct of the study, personal fees from Novartis, and personal fees from RAPPTA Therapeutics outside the submitted work. M. Mori reports grants from NCI and grants from AACR during the conduct of the study. B.M. Wolpin reports research funding from Celgene and Eli Lilly and consulting for BioLineRx, Celgene, G1 Therapeutics, and GRAIL. L.M. Coussens is a paid consultant for Cell Signaling Technologies, AbbVie, and Shasqi; received reagent and/or research support from Plexxikon, Pharmacyclics, Acerta Pharma LLC, Deciphera Pharmaceuticals LLC, Genentech, Roche Glycart AG, Syndax Pharmaceuticals, Innate Pharma, NanoString Technologies, and Cell Signaling Technologies; is a member of the Scientific Advisory Boards of Syndax Pharmaceuticals, Carisma Therapeutics, Zymeworks, Verseau Therapeutics, Cytomix Therapeutics, and Kineta; and is a member of the Lustgarten Therapeutics Advisory working group. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/8
Y1 - 2021/8
N2 - Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)-treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. Significance: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired.
AB - Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)-treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. Significance: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired.
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U2 - 10.1158/2159-8290.CD-20-0841
DO - 10.1158/2159-8290.CD-20-0841
M3 - Article
C2 - 33727309
AN - SCOPUS:85107469167
SN - 2159-8274
VL - 11
SP - 2014
EP - 2031
JO - Cancer discovery
JF - Cancer discovery
IS - 8
ER -