Expression of synthetic RNA-based gene circuits in tumors induces an antitumor T-cell response.
Major finding: Expression of synthetic RNA-based gene circuits in tumors induces an antitumor T-cell response.
Approach: Coactivation of tumor-specific promoters drives the coexpression of combinatorial immunomodulators.
Impact: Modular tumor-targeting RNA-based gene circuits hold promise as an immunotherapeutic approach.
Recent studies in the field of synthetic biology have described the design and construction of genetic circuits as logic-driven cancer gene therapies in which the genetic circuits integrate the activities of tumor-specific synthetic promoters and generate the output protein only when both input promoters are concurrently activated. To ascertain the immunotherapeutic potential of synthetic gene circuits, Nissim, Wu, and colleagues developed a modular synthetic RNA-based gene circuit platform that integrates the activity of two ovarian cancer–specific synthetic promoters, P1 and P2, which regulate genetic modules 1 and 2, respectively. Initially, activation of the synthetic MYC promoter S(cMYC)p in module 1 drove a miRNA-driven autoinhibitory loop and prevented expression of the reporter output gene mKate2; activation of the synthetic E2F1 promoter S(E2F1)p in module 2 resulted in the production of a sponge for the miRNA in module 1 to relieve the autoinhibition of module 1 and drive the expression of mKate2 and the module 2 reporter gene EGFP. To further enhance the tumor specificity of the genetic circuit, the modules were modified so that coactivation of S(cMYC)p and S(E2F1)p resulted in the expression of GAD, a synthetic transcription factor that drives the expression of target genes under the control of the synthetic promoter GALp, in ovarian cancer cells but not in other cells. Replacement of the target genes expressed by GAD with a gene encoding an surface T-cell engager (STE) resulted in T cell–specific secretion of IFNγ in vitro, and replacement with genes encoding the STE and the immunomodulatory genes CCL21, IL12, and anti–PD-1 antibody resulted in T cell–mediated inhibition of tumor growth and increased survival in vivo. Together, these findings describe a modular synthetic biology platform approach that is versatile and exhibits potential as an immunotherapeutic strategy.
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