Genomic and Immune Features in an Intrahepatic Cholangiocarcinoma Patient with Microsatellite Instability-High Suffered Rapid Acquired Resistance to PD-1 Inhibitor

Abstract

Introduction: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver malignancy with poor prognosis. Recently, the development of immune checkpoint inhibitors (ICIs), such as programmed cell death 1 (PD-1) inhibitors, has emerged as a promising strategy in multiple tumor types, including ICC. Microsatellite instability-high (MSI-H) is an important biomarker for ICIs in solid tumors. The response rate in patients with MSI-H is significantly higher than in those with microsatellite stability/microsatellite instability-low. And approximately 80-90% of the patients with MSI-H could maintain sustained clinical benefits once they had an initial response. However, some patients could have primary resistance at the beginning, and some might have acquired resistance after long-term treatment.

Case presentation: We present the case of an ICC patient with MSI-H who suffered rapid progression after a short-term remission with camrelizumab, a kind of PD-1 inhibitor, as second-line treatment. The patient's genomic and immune features were analyzed by next-generation sequencing and multiplex immunofluorescence staining to explore the possible mechanisms of the rapidly acquired resistance of ICIs in this MSI-H case.

Conclusion: The genomic and immunohistochemical analysis showed that TGFBR2 mutation, loss of HLA B44 supertype, carrying B62 supertype, and increased PD-L1⁺ cells, macrophages, and Tregs in the tumor microenvironment might be related to the nonsustain benefit of ICIs in this MSI-H patient.

Keywords: Intrahepatic cholangiocarcinoma; MSI-H; PD-1 inhibitor; Rapid acquired resistance.