An important hallmark of cancer is the ability to evade the immune system. Cell heterogeneity, inhibition of antigen presentation or immune cell infiltration allows immune surveillance evasion. For the first time, cell reprogramming offers exciting opportunities to overcome these challenges. My group has identified three transcription factors (TFs) sufficient to reprogram fibroblasts into dendritic cells (DCs). This proposal aims to test a cancer immunotherapy concept based on DC reprogramming and endowed antigen presenting cell (APC) function in tumor cells. First, I will define optimal TF combinations and external cues to efficiently reprogram human fibroblasts into DCs employing an innovative single-cell screen. Then, I will reprogram mouse and human tumor cells into tumor-APCs followed by characterization of transcriptome, chromatin accessibility, surface peptidome and ability to present antigens to T cells. Finally, I will test whether reprogrammed cells mount an attack against tumors in mouse models. I will test whether intratumoral delivery of reprogramming factors elicits in vivo antigen presentation, immune cell recruitment and tumor regression.
The approach proposed here will combine DCs’ antigen processing and presenting abilities with the endogenous generation of tumor antigens. This project represents a pioneering contribution by merging cell reprogramming and cancer immunotherapy, paving the way for an entirely new approach to cancer gene therapy.