A fluorescent biosensor-based platform for the discovery of immunogenic cancer cell death inducers

Area of Science:

• Immunology
• Oncology
• Drug Discovery

Background:

• Systemic anticancer immunity can be restored by inducing immunogenic cell death (ICD) in cancer cells.
• Cytotoxic drugs like anthracyclines, oxaliplatin, and taxanes can trigger ICD hallmarks, including calreticulin exposure and release of ATP, HMGB1, and type-1 interferons.

Purpose of the Study:

• To design a discovery pipeline for identifying novel ICD inducers.
• To utilize a phenotypic screening platform with fluorescent biosensors to detect ICD hallmarks.
• To accelerate the development of new immunotherapeutic agents.

Main Methods:

• Development of a phenotypic screening platform using fluorescent biosensors for ICD hallmarks.
• Automated screening of large chemical compound collections.
• Imaging-based assessment and phenotypic selection of potential ICD inducers.
• Validation of identified compounds in vitro and in vivo.
• Application of machine learning algorithms to analyze physicochemical properties of ICD inducers.

Main Results:

• Identification of novel compounds with the capacity to induce ICD.
• Validation of ICD inducers' ability to promote long-term immunological memory.
• Confirmation of ICD inducers' efficacy in conferring resistance against tumor rechallenge.
• Demonstration that machine learning can aid in preselecting compounds with ICD-stimulatory properties.

Conclusions:

• The developed screening pipeline effectively identifies novel ICD inducers.
• Validated ICD inducers can reinstate systemic anticancer immunity and confer tumor resistance.
• Machine learning integration enhances the efficiency of discovering new immunotherapeutic agents.