Silver nanoparticle induced immunogenic cell death can improve immunotherapy

Area of Science:

• Nanomedicine
• Immunology
• Oncology

Background:

• The tumor microenvironment (TME) often suppresses anti-cancer immune responses, limiting the efficacy of immunotherapies like immune checkpoint blockades (ICB).
• Strategies to convert 'cold' tumors to 'hot' tumors are crucial for improving ICB therapy outcomes.
• Combination therapies offer a promising approach to overcome TME-mediated immunosuppression.

Purpose of the Study:

• To screen metallic nanoparticles for their potential to modulate the TME and enhance anti-cancer immunity.
• To investigate the effects of silver nanoparticle (AgNP) core size and surface chemistry on cytotoxicity.
• To evaluate the therapeutic efficacy of Ag-citrate-5 nm nanoparticles in combination with anti-PD1 therapy for Renca tumors.

Main Methods:

• In vitro screening of metallic nanoparticles for cytotoxicity against tumor and non-tumor cell lines.
• Assessment of silver nanoparticle core size and surface chemistry effects on cytotoxicity.
• Analysis of reactive oxygen species (ROS) generation and cytokine production induced by AgNPs.
• In vitro and in vivo evaluation of calreticulin exposure as an immunogenic cell death (ICD) marker.
• In vivo treatment of subcutaneous Renca tumors with anti-PD1 alone or in combination with Ag-citrate-5 nm.
• Assessment of tumor size, necrosis, immune cell infiltration, and CD8+ T cell activity.

Main Results:

• Ag-citrate-5 nm nanoparticles demonstrated high cytotoxicity against Renca cells, mediated by excessive ROS generation and increased cytokine production.
• Ag-citrate-5 nm treatment induced calreticulin surface expression, a marker of ICD, both in vitro and in vivo.
• Combination therapy with anti-PD1 and Ag-citrate-5 nm significantly reduced tumor size and increased necrosis and immune cell infiltration.
• Therapeutic efficacy was dependent on cytotoxic CD8+ T cells, confirming their role in the anti-tumor response.

Conclusions:

• Ag-citrate-5 nm nanoparticles can overcome TME-induced immunosuppression by promoting ICD and enhancing immune cell influx.
• This nanoparticle-based approach sensitizes tumors to immune checkpoint blockade therapies.
• Ag-citrate-5 nm represents a promising therapeutic agent for combination strategies in cancer immunotherapy.