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<p>First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in <i>CTNNB1</i> (encoding for β-catenin), <i>AXIN1/2</i>, or <i>APC</i>, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting <i>CTNNB1</i> (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with <i>CTNNB1</i>-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in <i>CTNNB1</i>-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations.</p>

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Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月30日

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  • Brandon M. Lehrich,
  • Evan R. Delgado,
  • Tyler M. Yasaka,
  • Silvia Liu,
  • Catherine Cao,
  • Yuqing Liu,
  • Mohammad N. Taheri,
  • Xiangnan Guan,
  • Hartmut Koeppen,
  • Sucha Singh,
  • Vik Meadows,
  • Jia-Jun Liu,
  • Anya Singh-Varma,
  • Yekaterina Krutsenko,
  • Minakshi Poddar,
  • T. Kevin Hitchens,
  • Lesley M. Foley,
  • Binyong Liang,
  • Alex Rialdi,
  • Ravi P. Rai,
  • Panari Patel,
  • Madeline Riley,
  • Aaron Bell,
  • Reben Raeman,
  • Tulin Dadali,
  • Jason J. Luke,
  • Ernesto Guccione,
  • Mo R. Ebrahimkhani,
  • Amaia Lujambio,
  • Xin Chen,
  • Martin Maier,
  • Yulei Wang,
  • Wendy Broom,
  • Junyan Tao,
  • Satdarshan P. Monga

摘要

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations.