The expansion of techniques for genetic engineering has brought a new dimension for synthetic immunology. Immune cells are perfect candidates for such approaches because of their ability to patrol, to interact with many cell types, to proliferate upon activation and to differentiate in memory cells. For cancer cure in particular, they can be modified to eradicate tumor cells while counterbalancing the immunosuppressive tumor microenvironment.

The goal of our study is to implement a new synthetic circuit in B cells by lentiviral vector transduction, allowing the expression of therapeutic molecules in a temporally and spatially restricted manner controlled by the presence of tumor antigens. These molecules will increase inflammation locally and promote the differentiation of effector immune cells, thereby mediating tumor clearance.

We developed a synthetic circuit encoding a "sensor" (a membrane-anchored B-cell receptor, BCR, targeting a tumor antigen), a "transducer" (a promoter that can be induced by activated BCR) and "effector" molecules (e.g., the Interleukine 18). We isolated a 734 bp-long fragment of the NR4A1 promoter, which is specifically activated by the BCR signaling cascade in a fully reversible manner. By co-delivery of lentiviral vectors encoding respectively the transducer/effector and a sensor targeting ovalbumine, we achieved antigen-specific induction of the circuit. Indeed, the recognition of ovalbumine on the ectopic sensor specifically induced the activation of the NR4A1 promoter and the expression of the effector, demonstrating the circuit functionality in vitro. We are currently evaluating the ability of reprogrammed B cells to mediate tumor clearance in immunodeficient mice bearing human melanomas.