In vivo dendritic cell reprogramming for cancer immunotherapy [T cell scRNA + TCR]

Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced tumor regressions, and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy. Overall design: To characterize T cell responses elicited by in vivo cDC1 reprogramming, we profiled T cells from tumors, tdLN and blood using single cell 5'RNA and TCR-sequencing. At day 21, T cells were harvested from animals injected subcutaneously with PIB- or eGFP-transduced YUMM1.7 cells (1:1 mixed with parental cell line) and combined with anti-PD-1 or isotype control antibody treatment.