Related Experiment Video
Updated: Jun 25, 2025
Immunometabolic Circuits in Infection for Advancing Host Directed Therapies
Published on: September 13, 2024
A Synthetic Circuit Empowering Reprogrammed B Cells for Therapeutic Proteins Expression Regulated by Tumor Detection
Audrey Page1, Marie Delles, Didier Nègre
1CIRI - Centre International de Recherche en Infectiologie, Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France.
Abstract:
Cancer remains a leading cause of death worldwide, but immunotherapies hold promises to cure it by awaking the patient's immune system to provide long-term protection. Cell therapies, involving the infusion of immune cells, either directly or genetically modified, are being developed to recognize and destroy cancer cells. Here, we explored the potential of a new synthetic circuit to reprogram B cells to cure cancers. This circuit consists in a sensor (a membrane-anchored IgG1), a transducer (a fragment of the NR4A1 promoter) and an effector molecule. Upon recognition of its target, this sensor triggers signaling pathways leading to the activation of the transducer and to effector expression (here, a reporter molecule). We showed that this circuit could discriminate tumors expressing the target antigen from those that did not, in a dose dependent manner in vitro. Going further, we replaced the original membrane-anchored sensor by an immunoglobulin expression cassette that can not only be membrane-anchored but also be secreted depending on B-cell maturation status. This allowed concomitant activation of the circuit and secretion of transgenic antibodies directed against the targeted antigen. Of note, these antibodies could correctly bind their target and were recognized by FcR expressed at the surface of immune cells, which should synergically amplify the action of the effector. The potential of reprogrammed B cells remains to be assessed in vivo by implementing a therapeutic effector. In the future, B-cell reprogramming platforms should allow personalized cancer treatment by adapting both the sensor and the therapeutic effectors to patients.
Insights
Researchers reprogrammed B cells using a synthetic circuit for cancer immunotherapy. This engineered approach enables B cells to target and eliminate cancer cells, offering a promising avenue for personalized cancer treatments.
Area of Science:
- Immunology
- Synthetic Biology
- Oncology
Background:
- Cancer immunotherapy aims to harness the patient's immune system for long-term protection against malignancies.
- Cell therapies, including genetically modified immune cells, are under development for cancer treatment.
- B cells represent a potential cell type for reprogramming due to their immune functions.
Purpose of the Study:
- To explore the potential of a novel synthetic circuit for reprogramming B cells to treat cancer.
- To engineer B cells capable of recognizing and responding to cancer-specific antigens.
- To investigate the feasibility of using B cells as a platform for targeted cancer therapies.
Main Methods:
- Designed a synthetic circuit comprising a sensor (membrane-anchored IgG1), transducer (NR4A1 promoter fragment), and effector molecule.
- Validated the circuit's ability to discriminate target antigen-expressing tumors in vitro in a dose-dependent manner.
- Modified the sensor to an immunoglobulin expression cassette allowing membrane anchoring or secretion based on B-cell maturation.
Main Results:
- The synthetic circuit successfully demonstrated antigen-specific tumor recognition and response in vitro.
- The modified sensor enabled both circuit activation and secretion of antigen-specific antibodies.
- Secreted antibodies effectively bound their targets and were recognized by immune cell Fc receptors, suggesting synergistic immune activation.
Conclusions:
- Reprogrammed B cells utilizing a synthetic circuit show promise for cancer immunotherapy.
- The engineered B cells can act as targeted delivery vehicles for therapeutic antibodies.
- Future development of B-cell reprogramming platforms could lead to personalized cancer treatments tailored to individual patients.
Related Concept Videos
01:31Hybridoma Technology
Hybridoma Selection
Commonly used fusion techniques — electroporation,...
01:24Tagging and Fusion Proteins