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Background <p>Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited treatment options and a poor prognosis. Although immune checkpoint inhibitor (ICI)-based chemotherapy has recently been introduced as a first-line treatment, clinical responses remain highly variable. Currently, no reliable molecular biomarkers are available to predict the therapeutic efficacy of ICC.</p> Methods <p>We conducted a retrospective, multicenter cohort study of 25 patients with unresectable ICC treated with gemcitabine, cisplatin, and durvalumab (GCD therapy) between September 2022 and August 2024. Comprehensive genomic profiling was performed in 19 patients (76%) to identify genomic alterations. In selected cases, spatial transcriptomic analysis using the Xenium platform was employed to characterize tumor-immune spatial dynamics.</p> Results <p>The median progression-free survival (PFS) was 7.8&#xa0;months (95% CI: 3.6–10.6), and the median overall survival (OS) was 11.1&#xa0;months (95% CI: 6.9–18.6). Among genomic alterations, <i>TP53</i> mutation was the only independent predictor of shorter PFS in multivariate analysis (HR: 4.20; <i>p</i> = 0.036). <i>TP53</i>-mutant tumors were associated with significantly shorter PFS (<i>p</i> = 0.011) and a trend toward worse OS (<i>p</i> = 0.051). Spatial transcriptomic profiling revealed a distinct immunosuppressive microenvironment in <i>TP53</i>-mutated tumors marked by poor CD8⁺ T-cell infiltration, enrichment of CD109⁺ tumor-associated macrophages, and downregulation of antigen-presentation genes <i>TAP1</i> and <i>TAP2</i>.</p> Conclusions <p>This study is the first to identify <i>TP53</i> mutation as a biomarker of resistance to ICI-based therapy in ICC, and to uncover its immune-evasive phenotype using spatial profiling. These findings provide mechanistic insight into immune evasion and support the development of <i>TP53</i>-guided immunotherapeutic strategies in ICC.</p>

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TP53 mutation predicts resistance to immune checkpoint inhibitor-based therapy in intrahepatic cholangiocarcinoma

  • 期刊论文

  • 发表日期：

    2025年11月17日

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  • Hiroki Inada,
  • Sotaro Kurano,
  • Hideaki Miyamoto,
  • Masaya Onishi,
  • Yutaka Suzuki,
  • Satoshi Narahara,
  • Fumiya Otsuka,
  • Etsuko Iio,
  • Takehisa Watanabe,
  • Hiroko Setoyama,
  • Katsuya Nagaoka,
  • Toru Beppu,
  • Hiromitsu Hayashi,
  • Yasuhito Tanaka

摘要

Background

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited treatment options and a poor prognosis. Although immune checkpoint inhibitor (ICI)-based chemotherapy has recently been introduced as a first-line treatment, clinical responses remain highly variable. Currently, no reliable molecular biomarkers are available to predict the therapeutic efficacy of ICC.

Methods

We conducted a retrospective, multicenter cohort study of 25 patients with unresectable ICC treated with gemcitabine, cisplatin, and durvalumab (GCD therapy) between September 2022 and August 2024. Comprehensive genomic profiling was performed in 19 patients (76%) to identify genomic alterations. In selected cases, spatial transcriptomic analysis using the Xenium platform was employed to characterize tumor-immune spatial dynamics.

Results

The median progression-free survival (PFS) was 7.8 months (95% CI: 3.6–10.6), and the median overall survival (OS) was 11.1 months (95% CI: 6.9–18.6). Among genomic alterations, TP53 mutation was the only independent predictor of shorter PFS in multivariate analysis (HR: 4.20; p = 0.036). TP53-mutant tumors were associated with significantly shorter PFS (p = 0.011) and a trend toward worse OS (p = 0.051). Spatial transcriptomic profiling revealed a distinct immunosuppressive microenvironment in TP53-mutated tumors marked by poor CD8⁺ T-cell infiltration, enrichment of CD109⁺ tumor-associated macrophages, and downregulation of antigen-presentation genes TAP1 and TAP2.

Conclusions

This study is the first to identify TP53 mutation as a biomarker of resistance to ICI-based therapy in ICC, and to uncover its immune-evasive phenotype using spatial profiling. These findings provide mechanistic insight into immune evasion and support the development of TP53-guided immunotherapeutic strategies in ICC.