Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways
AuthorHo, Won Jin
Thomas, Dwayne L
Munday, Rebecca M
Armstrong, Todd D
Sztein, Marcelo B
Thompson, Elizabeth D
Jaffee, Elizabeth M
Fertig, Elana J
MetadataShow full item record
AbstractBackground: 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.
Keywordimmune regulatory pathways
Carcinoma, Pancreatic Ductal
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/15657
- Single-cell RNA sequencing reveals compartmental remodeling of tumor-infiltrating immune cells induced by anti-CD47 targeting in pancreatic cancer.
- Authors: Pan Y, Lu F, Fei Q, Yu X, Xiong P, Yu X, Dang Y, Hou Z, Lin W, Lin X, Zhang Z, Pan M, Huang H
- Issue date: 2019 Nov 27
- Integrated genomic and transcriptomic analysis reveals unique characteristics of hepatic metastases and pro-metastatic role of complement C1q in pancreatic ductal adenocarcinoma.
- Authors: Yang J, Lin P, Yang M, Liu W, Fu X, Liu D, Tao L, Huo Y, Zhang J, Hua R, Zhang Z, Li Y, Wang L, Xue J, Li H, Sun Y
- Issue date: 2021 Jan 4
- Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions.
- Authors: Lin W, Noel P, Borazanci EH, Lee J, Amini A, Han IW, Heo JS, Jameson GS, Fraser C, Steinbach M, Woo Y, Fong Y, Cridebring D, Von Hoff DD, Park JO, Han H
- Issue date: 2020 Sep 29
- Prognostic significance and immune infiltration of microenvironment-related signatures in pancreatic cancer.
- Authors: Lu Q, Zhang Y, Chen X, Gu W, Ji X, Chen Z
- Issue date: 2021 Mar 26
- Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes.
- Authors: de Koning W, Latifi D, Li Y, van Eijck CHJ, Stubbs AP, Mustafa DAM
- Issue date: 2021