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<p>Cytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy.</p>

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Palbociclib and dsRNA sensor co-operate to enhance anti-cancer effects through ER stress and modulation of immune evasion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月25日

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  • Victoria Roulstone,
  • Joan Kyula-Currie,
  • James Wright,
  • Emmanuel C. Patin,
  • Isaac Dean,
  • Lu Yu,
  • Aida Barreiro-Alonso,
  • Miriam Melake,
  • Jyoti Choudhary,
  • Richard Elliott,
  • Christopher J. Lord,
  • David Mansfield,
  • Nik Matthews,
  • Ritika Chauhan,
  • Victoria Jennings,
  • Charleen Chan Wah Hak,
  • Holly Baldock,
  • Francesca Butera,
  • Elizabeth Appleton,
  • Pablo Nenclares,
  • Malin Pedersen,
  • Shane Foo,
  • Amarin Wongariyapak,
  • Antonio Rullan,
  • Tencho Tenev,
  • Pascal Meier,
  • Richard Vile,
  • Hardev Pandha,
  • Alan Melcher,
  • Martin McLaughlin,
  • Kevin J. Harrington

摘要

Cytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy.