Developing novel single-cell technologies to model and perturb intra-tumor interactions and signaling – an innovation program for the next generation of immunotherapies

Single-cell genomic technologies have transformed many fields of research. We here seek to do just that in synthetic-immunology and immunotherapy. At present, our understanding of the complex crosstalk within the tumor microenvironment (TME) is still piecemeal, as is our ability to effectively engineer the immune system to attack tumor cells in spite of the robust immune-suppression signaling of the tumor. In line, current immunotherapies are effective only in a small subset of tumor types and patients, emphasizing the dire need to better understand immune-suppressive mechanisms within the TME and develop new immunotherapy strategies. What if we could develop technologies that reprogram the immune system to suit our therapeutic needs? In TROJAN-Cell, we will do so by first uncovering fundamental principles of the immune-tumor niche using advanced single-cell multiomics tools and modelling approaches. This will then serve to develop TROJAN-Cella novel synthetic immunology technology for engineering circuits capable of sensing inhibitory-immune signals and generating a proportional self-regulated immune-activation responsethus using the tumors own pro-cancer signaling to eradicate it. In Obj.1, we will dissect the principles of the inhibitory crosstalk and signaling in the TME of diverse human tumors using our single-cell technologies PIC-seq and INs-seq. In Obj.2, we will screen and develop mice tumor models that recapitulate the human TME, which we will use to define the function of factors/circuits of interest. In Obj.3, we will develop TROJAN-Cell, a novel toolset for transforming tumor inhibitory signals into potent, highly specific anti-tumor immunity. Our research will greatly expand our understanding of the immune-inhibitory crosstalk in the TME and give rise to novel immune engineering approaches and molecules, which may serve as the next generation of cancer immunotherapies.