Journal Article

Hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins

Tariveranmoshabad, Mito, Xue, Yuqing, Zingone, Sofia K., Lee, Jae W., Stone, Meredith L., Balachandran, Vinod P., Choi, Hana, Herrera, Veronica M., Choi-Bose, Shaanti, Wattenberg, Max M., Lee, Jesse, Coho, Heather, Patel, Dhruv, Markowitz, Kelly, Beatty, Gregory L., Delman, Devora

2024

Overview

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8 + T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer. Here the authors show how the liver affects the immune response to pancreatic ductal adenocarcinoma and that cancer immunity and survival outcomes after surgery might be bolstered by therapeutic intervention on hepatocyte release of serum amyloid A proteins.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554/1834 / 631/250/2161 / 631/67/580/1884 / Adenocarcinoma / Amyloid / Animals / Biomedical and Life Sciences / Biomedicine / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - pathology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line, Tumor / Cytokines / Dendritic cells / Dendritic Cells - immunology / Dendritic Cells - metabolism / Hepatocytes / Hepatocytes - immunology / Hepatocytes - metabolism / Humans / Immune response / Immunology / Infectious Diseases / Infiltration / Interleukin 6 / Interleukin-6 - metabolism / Letter / Liver / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Metastases / Mice / Mice, Inbred C57BL / Mice, Knockout / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - metabolism / Proteins / Serum Amyloid A Protein - genetics / Serum Amyloid A Protein - metabolism / Signal Transduction / Solid tumors / Stat3 protein / STAT3 Transcription Factor - metabolism / Surgery / Surveillance / Toll-like receptors / Tumor Escape / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors