TY - JOUR
T1 - A four-chemokine signature is associated with a T-cell- inflamed phenotype in primary and metastatic pancreatic cancer
AU - Romero, Joan M.
AU - Grünwald, Barbara
AU - Jang, Gun Ho
AU - Bavi, Prashant P.
AU - Jhaveri, Aaditeya
AU - Masoomian, Mehdi
AU - Fischer, Sandra E.
AU - Zhang, Amy
AU - Denroche, Robert E.
AU - Lungu, Ilinca M.
AU - De Luca, Angela
AU - Bartlett, John M.S.
AU - Xu, Jing
AU - Li, Niandong
AU - Dhaliwa, Sharon
AU - Liang, Sheng Ben
AU - Chadwick, Dianne
AU - Vyas, Foram
AU - Bronsert, Peter
AU - Khokha, Rama
AU - McGaha, Tracy L.
AU - Notta, Faiyaz
AU - Ohashi, Pamela S.
AU - Done, Susan J.
AU - O'Kane, Grainne M.
AU - Wilson, Julie M.
AU - Knox, Jennifer J.
AU - Connor, Ashton
AU - Wang, Yifan
AU - Zogopoulos, George
AU - Gallinger, Steven
N1 - Funding Information:
This study was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, and the Canadian Cancer Society Research Institute. The study was also supported by charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation. S. Gallinge is the recipient of an Investigator Award from OICR and the Lebovic Chair in Hepatobiliary/pancreatic Surgical Oncology. J.M. Romero was supported by a Canadian Institutes of Health Research CGSM studentship. B. Gru€nwald was supported by the Princess Margaret Cancer Foundation, the European Molecular Biology Organization (ALTF 116-2018), and the Alexander von Humboldt Foundation (DEU 1199182 FLF-P). G. Zogopoulos is a clinical research scholar of the Fonds de recherche du Québec, Santé. We acknowledge the contributions of team members from the OICR Genomics and Bioinformatics platform (genomics. oicr.on.ca). We also thank the following individuals who provided patient samples: Jim Biagi and Sulaiman Nanji, Kingston General Hospital, Kingston, ON, Canada; Gloria M. Petersen, Mayo Clinic College of Medicine, Rochester, MN, USA.
Funding Information:
This study was conducted with the support of the Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) through funding provided by the Government of Ontario, the Wallace McCain Centre for Pancreatic Cancer supported by the Princess Margaret Cancer Foundation, the Terry Fox Research Institute, and the Canadian Cancer Society Research Institute. The study was also supported by charitable donations from the Canadian Friends of the Hebrew University (Alex U. Soyka) and the Pancreatic Cancer Canada Foundation. S. Gallinge is the recipient of an Investigator Award from OICR and the Lebovic Chair in Hepatobiliary/pancreatic Surgical Oncology. J.M. Romero was supported by a Canadian Institutes of Health Research CGSM studentship. B. Gr?nwald was supported by the Princess Margaret Cancer Foundation, the European Molecular Biology Organization (ALTF 116-2018), and the Alexander von Humboldt Foundation (DEU 1199182 FLF-P). G. Zogopoulos is a clinical research scholar of the Fonds de recherche du Quebec, Sante. We acknowledge the contributions of team members from the OICR Genomics and Bioinformatics platform (genomics. oicr.on.ca). We also thank the following individuals who provided patient samples: Jim Biagi and Sulaiman Nanji, Kingston General Hospital, Kingston, ON, Canada; Gloria M. Petersen, Mayo Clinic College of Medicine, Rochester, MN, USA.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/4/15
Y1 - 2020/4/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-2803
DO - 10.1158/1078-0432.CCR-19-2803
M3 - Article
C2 - 31964786
AN - SCOPUS:85082516119
SN - 1078-0432
VL - 26
SP - 1997
EP - 2010
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -