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Tytuł:
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A Four-Chemokine Signature Is Associated with a T-cell-Inflamed Phenotype in Primary and Metastatic Pancreatic Cancer.
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Autorzy:
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Romero JM; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Grünwald B; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Jang GH; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Bavi PP; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Jhaveri A; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Masoomian M; Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
Fischer SE; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.; Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
Zhang A; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Denroche RE; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Lungu IM; Diagnostic Development, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
De Luca A; Diagnostic Development, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Bartlett JMS; Diagnostic Development, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Xu J; Drug Development Program Biomarker Laboratory, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Li N; UHN Biobank, University Health Network, Toronto, Ontario, Canada.
Dhaliwal S; UHN Biobank, University Health Network, Toronto, Ontario, Canada.
Liang SB; UHN Biobank, University Health Network, Toronto, Ontario, Canada.
Chadwick D; UHN Biobank, University Health Network, Toronto, Ontario, Canada.
Vyas F; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Bronsert P; Tumorbank Comprehensive Cancer Center Freiburg, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Institute for Surgical Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Khokha R; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
McGaha TL; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Notta F; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Ohashi PS; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Done SJ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.; Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
O'Kane GM; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.; Wallace McCain Centre of Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Wilson JM; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Knox JJ; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.; Wallace McCain Centre of Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Connor A; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Wang Y; The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.; The Goodman Cancer Research Centre of McGill University, Montréal, Québec, Canada.
Zogopoulos G; The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.; The Goodman Cancer Research Centre of McGill University, Montréal, Québec, Canada.
Gallinger S; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. .; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.; Wallace McCain Centre of Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.; Department of Surgery, University of Toronto, Toronto, Ontario, Canada.; Hepatobilliary Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada.
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Źródło:
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Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Apr 15; Vol. 26 (8), pp. 1997-2010. Date of Electronic Publication: 2020 Jan 21.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Denville, NJ : The Association, c1995-
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MeSH Terms:
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Biomarkers, Tumor/*genetics
CD8-Positive T-Lymphocytes/*immunology
Chemokine CCL4/*genetics
Chemokine CCL5/*genetics
Chemokine CXCL10/*genetics
Chemokine CXCL9/*genetics
Liver Neoplasms/*secondary
Pancreatic Neoplasms/*pathology
Biomarkers, Tumor/immunology ; Chemokine CCL4/immunology ; Chemokine CCL5/immunology ; Chemokine CXCL10/immunology ; Chemokine CXCL9/immunology ; Cohort Studies ; Computational Biology/methods ; Databases, Genetic/statistics & numerical data ; Humans ; Immune Checkpoint Proteins/genetics ; Immunotherapy/methods ; Liver Neoplasms/genetics ; Liver Neoplasms/immunology ; Mutation ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/immunology ; RNA-Seq/methods
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Grant Information:
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R01 CA190449 United States CA NCI NIH HHS; Canada CIHR
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Substance Nomenclature:
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0 (Biomarkers, Tumor)
0 (CCL4 protein, human)
0 (CCL5 protein, human)
0 (CXCL10 protein, human)
0 (CXCL9 protein, human)
0 (Chemokine CCL4)
0 (Chemokine CCL5)
0 (Chemokine CXCL10)
0 (Chemokine CXCL9)
0 (Immune Checkpoint Proteins)
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Entry Date(s):
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Date Created: 20200123 Date Completed: 20210127 Latest Revision: 20211111
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Update Code:
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20240104
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DOI:
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10.1158/1078-0432.CCR-19-2803
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PMID:
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31964786
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Purpose: The molecular drivers of antitumor immunity in pancreatic ductal adenocarcinoma (PDAC) are poorly understood, posing a major obstacle for the identification of patients potentially amenable for immune-checkpoint blockade or other novel strategies. Here, we explore the association of chemokine expression with effector T-cell infiltration in PDAC.
Experimental Design: Discovery cohorts comprised 113 primary resected PDAC and 107 PDAC liver metastases. Validation cohorts comprised 182 PDAC from The Cancer Genome Atlas and 92 PDACs from the Australian International Cancer Genome Consortium. We explored associations between immune cell counts by immunohistochemistry, chemokine expression, and transcriptional hallmarks of antitumor immunity by RNA sequencing (RNA-seq), and mutational burden by whole-genome sequencing.
Results: Among all known human chemokines, a coregulated set of four ( CCL4, CCL5, CXCL9 , and CXCL10 ) was strongly associated with CD8 + T-cell infiltration ( P < 0.001). Expression of this "4-chemokine signature" positively correlated with transcriptional metrics of T-cell activation ( ZAP70, ITK , and IL2RB ), cytolytic activity ( GZMA and PRF1 ), and immunosuppression ( PDL1, PD1, CTLA4, TIM3, TIGIT, LAG3, FASLG , and IDO1 ). Furthermore, the 4-chemokine signature marked tumors with increased T-cell activation scores (MHC I presentation, T-cell/APC costimulation) and elevated expression of innate immune sensing pathways involved in T-cell priming (STING and NLRP3 inflammasome pathways, BATF3-driven dendritic cells). Importantly, expression of this 4-chemokine signature was consistently indicative of a T-cell-inflamed phenotype across primary PDAC and PDAC liver metastases.
Conclusions: A conserved 4-chemokine signature marks resectable and metastatic PDAC tumors with an active antitumor phenotype. This could have implications for the appropriate selection of PDAC patients in immunotherapy trials.
(©2020 American Association for Cancer Research.)
