Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways.

Autor:	Ho WJ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA.; The Johns Hopkins Cancer Convergence Institute, Baltimore, USA.; Skip Viragh Center for Pancreatic Cancer, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, 4M07 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21287, USA., Erbe R; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA., Danilova L; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Phyo Z; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Bigelow E; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Stein-O'Brien G; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA., Thomas DL 2nd; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, USA., Charmsaz S; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Gross N; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Woolman S; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Cruz K; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Munday RM; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA., Zaidi N; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA.; Skip Viragh Center for Pancreatic Cancer, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, 4M07 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21287, USA., Armstrong TD; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Sztein MB; Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA., Yarchoan M; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA., Thompson ED; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA.; Skip Viragh Center for Pancreatic Cancer, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, 4M07 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21287, USA.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA., Jaffee EM; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA. ejaffee@jhmi.edu.; The Johns Hopkins Cancer Convergence Institute, Baltimore, USA. ejaffee@jhmi.edu.; Skip Viragh Center for Pancreatic Cancer, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, 4M07 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21287, USA. ejaffee@jhmi.edu., Fertig EJ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 550 N Broadway Suite 1101E, Baltimore, MD, 21209, USA. ejfertig@jhmi.edu.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA. ejfertig@jhmi.edu.; Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA. ejfertig@jhmi.edu.; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, USA. ejfertig@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Genome biology [Genome Biol] 2021 May 13; Vol. 22 (1), pp. 154. Date of Electronic Publication: 2021 May 13.
DOI:	10.1186/s13059-021-02363-6
Abstrakt:	Background: The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed at the metastatic stage, and standard therapies have limited activity with a dismal 5-year survival rate of only 8%. The liver and lung are the most common sites of PDAC metastasis, and each have been differentially associated with prognoses and responses to systemic therapies. A deeper understanding of the molecular and cellular landscape within the tumor microenvironment (TME) metastasis at these different sites is critical to informing future therapeutic strategies against metastatic PDAC. Results: By leveraging combined mass cytometry, immunohistochemistry, and RNA sequencing, we identify key regulatory pathways that distinguish the liver and lung TMEs in a preclinical mouse model of metastatic PDAC. We demonstrate that the lung TME generally exhibits higher levels of immune infiltration, immune activation, and pro-immune signaling pathways, whereas multiple immune-suppressive pathways are emphasized in the liver TME. We then perform further validation of these preclinical findings in paired human lung and liver metastatic samples using immunohistochemistry from PDAC rapid autopsy specimens. Finally, in silico validation with transfer learning between our mouse model and TCGA datasets further demonstrates that many of the site-associated features are detectable even in the context of different primary tumors. Conclusions: Determining the distinctive immune-suppressive features in multiple liver and lung TME datasets provides further insight into the tissue specificity of molecular and cellular pathways, suggesting a potential mechanism underlying the discordant clinical responses that are often observed in metastatic diseases.
Databáze:	MEDLINE
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