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Leukocyte Heterogeneity in Pancreatic Ductal Adenocarcinoma: Phenotypic and Spatial Features Associated with Clinical Outcome
Open accessPublished version of a preprint
Abstract
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. This article is highlighted in the In This Issue feature, p. 1861
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“Fortunately, advances in multiplexed immunohistochemical staining and imaging technology have enabled the expansion of markers that can be used in spatial assessment of cancer cell number, function and evolutionary trajectories273,274.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [274]
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Metadata
- Authors
- Liudahl, S. M., Betts, C. B., Sivagnanam, S., Morales-Oyarvide, V., da Silva, A., Yuan, C., Hwang, S., Grossblatt-Wait, A., Leis, K. R., Larson, W., Lavoie, M. B., Robinson, P., Dias Costa, A., Väyrynen, S. A., Clancy, T. E., Rubinson, D. A., Link, J., Keith, D., Horton, W., Tempero, M. A., Vonderheide, R. H., Jaffee, E. M., Sheppard, B., Goecks, J., Sears, R. C., Park, B. S., Mori, M., Nowak, J. A., Wolpin, B. M., & Coussens, L. M.
- Affiliations
- Oregon Health & Science University (US)
- 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- University of California, San Francisco (US)
- University of Pennsylvania (US)
- Johns Hopkins University (US)
- Corresponding author
- Coussens, Lisa M.
- ORCID
- Liudahl, Shannon M.
- Betts, Courtney B.
- Sivagnanam, Shamilene
- da Silva, Annacarolina
- Yuan, Chen
- Grossblatt-Wait, Alison
- Väyrynen, Sara A.
- Clancy, Thomas E.
- Rubinson, Douglas A.
- Link, Jason
- Keith, Dove
- Horton, Wesley
- Tempero, Margaret A.
- Vonderheide, Robert H.
- Jaffee, Elizabeth M.
- Sheppard, Brett
- Goecks, Jeremy
- Sears, Rosalie C.
- Park, Byung S.
- Mori, Motomi
- Nowak, Jonathan A.
- Wolpin, Brian M.
- Coussens, Lisa M.
- Venue
- Cancer Discovery
- Published
- 2021-03-16
- Volume
- 11
- Issue
- 8
- Pages
- 2014-2031
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8338775
- OpenAlex
- W3136861954
- Cited by
- 164
- References
- 52
- Citations by year
- 2026: 31 · 2025: 26 · 2024: 34 · 2023: 40 · 2022: 20 · 2021: 13
- FWCI
- 9.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Stand Up To Cancer—Lustgarten Foundation Pancreatic Cancer Dream Team Translational Research Grant (SU2C-AACR-DT14-14)
- National Institutes of Health (1U01 CA224012, U2C CA233280, R01 CA223150, R01 CA226909, R21 HD099367, UL1TR002369)
- National Cancer Institute Human Tumor Atlas Network (U2C CA233280)
- NIH (U01 CA210171, P50 CA127003, 1U01 CA224012, U2C CA233280, U54 CA209988, R01 CA196228, R01 CA186241)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- pancreatic ductal adenocarcinoma, tumor immune microenvironment, leukocyte heterogeneity, myeloid cells, lymphoid cells, neoadjuvant therapy, predictive biomarkers, clinical outcomes, metastatic pancreatic cancer, tissue microarray, single-cell profiling
- MeSH terms
- Humans, Immunotherapy, Leukocytes, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Tumor Microenvironment
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