Myeloid cell‐based delivery of IFN‐γ reprograms the leukemia microenvironment and induces anti‐tumoral immune responses

• Main Authors: Adele Mucci, Gabriele Antonarelli, Carolina Caserta, Francesco Maria Vittoria, Giacomo Desantis, Riccardo Pagani, Beatrice Greco, Monica Casucci, Giulia Escobar, Laura Passerini, Nico Lachmann, Francesca Sanvito, Matteo Barcella, Ivan Merelli, Luigi Naldini, Bernhard Gentner
• Format: Article
• Language: English
• Published: Wiley 2021-10-01
• Series: EMBO Molecular Medicine
• Subjects: ex vivo gene therapy; immunotherapy; interferon‐gamma; leukemia; Tie2‐expressing monocytes
• Online Access: https://doi.org/10.15252/emmm.202013598

Abstract 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‐γ (IFN‐γ) reduced tumor progression in mouse models of B‐cell acute lymphoblastic leukemia (B‐ALL) and colorectal carcinoma (MC38). Its activity depended on the immune system's capacity to respond to IFN‐γ and drove the counter‐selection of leukemia cells expressing surrogate antigens. Gene‐based IFN‐γ 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‐γ was further enhanced by either co‐delivery of tumor necrosis factor‐α (TNF‐α) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.