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

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Cytoplasmic pattern recognition receptors (PRRs) like RIG-I/MDA5 are crucial for antiviral responses.
• Oncolytic viruses and targeted therapies are investigated for cancer treatment.

Purpose of the Study:

• To screen for synergistic drug-virotherapy combinations for enhanced anti-cancer efficacy.
• To investigate the interplay between RNA-sensing pathways, ER stress, and innate immune activation in cancer cells.

Main Methods:

• Screening of synergistic drug-virotherapy combinations using reovirus type III Dearing strain (Rt3D) and palbociclib.
• Analysis of interferon production, signaling, innate immune activation, and HLA expression.
• Investigation of epigenetic landscape, endogenous retroviral (ERV) elements, and immunopeptidome alterations.

Main Results:

• The Rt3D-palbociclib combination synergistically augments oncolytic virus-induced stress responses and interferon production.
• Crosstalk between RNA-sensing and ER stress pathways enhances cancer cell death and interferon production.
• Combined therapy increases innate immune activation, IFN-induced HLA expression, and alters epigenetic/ERV landscapes, impacting the immunopeptidome.

Conclusions:

• The combination of Rt3D and palbociclib demonstrates enhanced anti-cancer efficacy through synergistic activation of stress and PRR pathways.
• Findings highlight the crosstalk between stress signaling and PRR activation as a key mechanism for improved anti-cancer outcomes.
• This approach offers a potential strategy for enhancing oncolytic virotherapy by modulating innate immune responses and tumor microenvironment.