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 (MSS/MSI-L). And approximately 80% to 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 (mIF) to explore the possible mechanisms of the rapidly acquired resistance of ICIs in this MSI-H case. Discussion/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 non-sustain benefit of ICIs in this MSI-H patient.


中文翻译：

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具有高微卫星不稳定性且对 PD-1 抑制剂快速产生耐药性的肝内胆管癌患者的基因组和免疫特征

简介：肝内胆管癌（ICC）是一种高度侵袭性的肝脏恶性肿瘤，预后较差。最近，免疫检查点抑制剂（ICIs）的开发，例如程序性细胞死亡1（PD-1）抑制剂，已成为包括ICC在内的多种肿瘤类型的一种有前途的策略。微卫星不稳定性高 (MSI-H) 是实体瘤 ICI 的重要生物标志物。MSI-H 患者的缓解率显着高于微卫星稳定性/微卫星不稳定性低 (MSS/MSI-L) 患者。大约 80% 至 90% 的 MSI-H 患者一旦获得初步缓解，就能保持持续的临床获益。但有的患者一开始就可能产生原发性耐药，有的则可能在长期治疗后产生耐药性。病例介绍：我们介绍了一名患有 MSI-H 的 ICC 患者的病例，该患者在使用 Camrelizumab（一种 PD-1 抑制剂）作为二线治疗短期缓解后病情迅速恶化。通过二代测序和多重免疫荧光染色（mIF）分析患者的基因组和免疫特征，以探讨该 MSI-H 病例中 ICI 快速获得耐药性的可能机制。讨论/结论：基因组和免疫组化分析表明，TGFBR2突变、HLA B44超型缺失、携带B62超型以及肿瘤微环境中PD-L1+细胞、巨噬细胞和Treg细胞增加可能与ICIs的非持续获益有关。这位 MSI-H 患者。