Exosomal circ-PTPN22 and circ-ADAMTS6 mark T cell exhaustion and neutrophil extracellular traps in Asian intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is a liver tumor featured by challenges of non-invasive early diagnosis and a higher prevalence rate in Asian countries. These characteristics necessitate the development of liquid biopsy and immunotherapy methods to improve the prognosis of patients with ICC. Herein, we conducted a pilot study on the transcriptome of tumor tissues, adjacent normal tissues, and plasma exosomes of Asian patients with ICC from northern and southern China. We identified a subgroup of immunogenic Asian ICC, which is different from Caucasian ICC and is characterized by T cell exhaustion and neutrophil extracellular traps. The levels of circ-PTPN22 (hsa_circ_0110529) and circ-ADAMTS6 (hsa_circ_0072688), potential circRNA biomarkers, were elevated in the ICC tumor tissues and plasma exosomes of this subgroup than in the other subgroups and normal controls. These circRNAs were derived from post-transcriptional backsplicing of PTPN22 and ADAMTS6 that were expressed in T cells and endothelial cells, respectively, in the ICC microenvironment. Our results revealed a subgroup of Asian ICC characterized by T cell exhaustion and neutrophil extracellular traps and marked by elevated levels of circ-PTPN22 and circ-ADAMTS6 in tumor tissues and plasma exosomes. This subgroup is potentially detectable by plasma exosomal circRNAs and treatable with immune checkpoint blockade.