Journal Article

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

Charmsaz, Soren, Stein-O’Brien, Genevieve, Thomas, Dwayne L., Sztein, Marcelo B., Yarchoan, Mark, Woolman, Skylar, Thompson, Elizabeth D., Armstrong, Todd D., Jaffee, Elizabeth M., Cruz, Kayla, Ho, Won Jin, Zaidi, Neeha, Erbe, Rossin, Phyo, Zaw, Munday, Rebecca M., Gross, Nicole, Bigelow, Emma, Fertig, Elana J., Danilova, Ludmila

2021

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: adenocarcinoma / Animal Genetics and Genomics / Animals / Autopsy / Bioinformatics / Biomedical and Life Sciences / Cancer Evolution and Metastasis / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - immunology / Cell Line, Tumor / Chemokines - metabolism / computer simulation / Cytometry / Cytotoxicity / data collection / Disease Models, Animal / Evolutionary Biology / Female / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / genome / Genomics / Human Genetics / Humans / Immune response / Immunohistochemistry / Immunosuppression Therapy / landscapes / Life Sciences / Liver / Liver cancer / liver neoplasms / Liver Neoplasms - genetics / Liver Neoplasms - immunology / Liver Neoplasms - pathology / Lung Neoplasms - secondary / Lungs / Lymphocytes / Medical prognosis / Metastases / Metastasis / Mice / Mice, Inbred C57BL / Microbial Genetics and Genomics / Microenvironments / Mutation / necropsy / Neoplasm Metastasis / Pancreatic cancer / pancreatic neoplasms / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - pathology / Plant Genetics and Genomics / RNA / Signal Transduction / survival rate / T-Lymphocytes - immunology / therapeutics / Transfer learning / Tumor microenvironment / Tumor Microenvironment - genetics / Tumor Microenvironment - immunology / Tumors