HEPATOCYTES COORDINATE A SYSTEMIC ENDOCRINE NETWORK IN CANCER
Serum Amyloid A
T cell infiltration into tumors is a favorable prognostic feature. However, the majority of solid tumors lack productive tumor T cell immunity, and the mechanisms that coordinate T cell exclusion remain incompletely understood. Accumulating evidence suggests that while cancer cell intrinsic and tumor microenvironmental cues contribute to immune suppression, tumor extrinsic mechanisms directed by distant organs also play a critical role in determining tumor and systemic immunity. Here, we show that liver activation, specifically interleukin (IL)-6/STAT3 signaling in hepatocytes, regulates T cell surveillance and pro-metastatic conditioning in cancer and, ultimately, survival and response to standard of care therapies. We found that primary tumor development alters the liver microenvironment, marked by an accumulation of Ly6G+ granulocytes and F4/80+ macrophages, increased deposition of fibronectin, and upregulation of the IL-6/JAK/STAT3 pathway. Subsequent transcriptomic analysis of STAT3 deficient livers identified hepatocyte-derived acute phase reactants serum amyloid A proteins 1 & 2 (SAA) as key determinants of liver directed inflammation. Genetic ablation of SAA receptor toll-like receptor 2 (TLR2) or the TLR signaling adaptor MyD88 reversed these microenvironmental changes in the liver. Notably, loss of STAT3 in hepatocytes or genetic ablation of SAA also induced remodeling of the primary tumor immune microenvironment, resulting in an influx of tumor specific CD8+ T cells into primary tumors and inhibited tumor growth. Moreover, overexpression of IL-6 in hepatocytes was sufficient to inhibit T cell infiltration into primary tumors. Finally, treatment of SAA deficient mice with either chemotherapy or a single dose of a STING agonist in combination with PD-1 checkpoint blockade significantly suppressed tumor growth and extended overall survival. Taken together, these findings establish a pivotal endocrine-tumor network that links liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer and favorable responses to cancer therapies.