Background Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 to treat cancer has revolutionized immuno-oncology. However, therapy is limited by frequent immune-related adverse events, including hepatitis (irHepatitis), which occurs in ~1–17% of patients. While irHepatitis is often mild, it can cause severe hepatic dysfunction, lead to delays in cancer therapy, and is often treated with immunosuppressive agents that may compromise anti-tumor immune responses. irHepatitis shares clinical and histologic features with autoimmune hepatitis (AIH). The study of irHepatitis and AIH is therefore important for understanding how immune tolerance is lost across a spectrum of inflammatory human liver diseases.
Methods To characterize the cellular and molecular underpinnings of irHepatitis, we used single-cell and single-nuclei RNA sequencing with paired T-cell receptor and B-cell receptor sequencing to characterize ~300,000 cells from the liver and blood of 23 patients (9 irHepatitis, 4 AIH, 3 controls on ICB, 7 controls not on ICB). irHepatitis was defined by a hepatocellular or cholestatic rise in liver function tests and centrilobular or panlobular histiocytic liver injury requiring steroids. Controls had drug-induced liver injury, hepatic steatosis, non-alcoholic steatohepatitis, primary biliary cirrhosis, or venous outflow obstruction not requiring immunosuppression. This study was approved by the DANA-Farber/Harvard Cancer Center Institutional Review Boards (DFCI/HCC 11–181 and 13–416, Mass General Brigham 2010P001242). All study participants gave informed consent before enrolling in this study.
Results In irHepatitis, we detected clonally-related, liver T cells expressing CXCL13 and expanded cycling and cytotoxic CD8 T cells that spanned effector to exhausted phenotypes. Parallel analysis of tissue immune cells from patients with AIH or irHepatitis enabled the identification of cell types and states both common and unique to each type of immune-mediated liver injury. Analysis of matched blood samples from the same patient cohort revealed how cellular and transcriptional signatures in the liver were mirrored in circulating immune cells. Lastly, analysis of hepatocytes, cholangiocytes, and mesenchymal cells revealed inflammatory signatures suggesting liver parenchymal dysfunction.
Conclusions In defining the cellular and transcriptional programs that are altered in irHepatitis and AIH, we have identified novel pathways that could be therapeutically targeted to treat liver inflammation and have determined how PD-1 and CTLA-4 signaling may contribute to immune tolerance in the liver.
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