| Abstract: |
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. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. |
| Keywords: |
signal transduction; cancer survival; controlled study; human tissue; cancer surgery; human cell; major clinical study; genetics; splenectomy; hepatitis; cancer growth; nonhuman; note; pancreatic neoplasms; transcription factor foxp3; cd8+ t lymphocyte; tumor associated leukocyte; cd8-positive t-lymphocytes; lymphocytes, tumor-infiltrating; protein blood level; animal cell; mouse; animal; metabolism; animals; mice; mice, knockout; animal tissue; hepatocytes; stat3 protein; metastasis; dendritic cell; carcinoma, pancreatic ductal; animal experiment; animal model; pathology; cell line, tumor; mice, inbred c57bl; cancer survivor; c57bl mouse; immunology; dendritic cells; pancreas tumor; cd4+ t lymphocyte; cytotoxic t lymphocyte; tumor cell line; interleukin 6; interleukin-6; protein secretion; stat3 transcription factor; cytokine production; liver cell; lymphocytic infiltration; immunosurveillance; cell activation; toll like receptor 2; distal pancreatectomy; knockout mouse; tumor microenvironment; immune evasion; pancreatic ductal carcinoma; tumor escape; serum amyloid a; long term survival; saa2 protein, mouse; serum amyloid a protein; humans; human; rna sequencing; tlr signaling; malignant neoplasm; jak-stat signaling
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