Myeloid cell-based delivery of IFN-? reprograms leukemia microenvironment and induces anti-tumoral immune responses

The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that Interferon-? (IFN?) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity was dependent on the capacity of the immune system to respond to IFN? and drove counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFN? delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFN? was further enhanced by either co-delivery of tumor necrosis factor a (TNFa) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses. Overall design: We undertook an unbiased transcriptional characterization of the B-ALL immune microenvironment performing 10x single cell RNA sequencing (scRNAseq) on total BM cells from mice treated or not with IFN? gene therapy