Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens

• Published in: Nature communications Vol. 9; no. 1; pp. 2896 - 16
• Main Authors: Escobar, Giulia, Barbarossa, Luigi, Barbiera, Giulia, Norelli, Margherita, Genua, Marco, Ranghetti, Anna, Plati, Tiziana, Camisa, Barbara, Brombin, Chiara, Cittaro, Davide, Annoni, Andrea, Bondanza, Attilio, Ostuni, Renato, Gentner, Bernhard, Naldini, Luigi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/100; 13/31; 13/44; 38/91; 42/41; 631/67/1059/2325; 631/67/327; 631/67/580; 64/60; Animals; Anticancer properties; Antigen (tumor-associated); Antigens; Antigens, Neoplasm - immunology; Antitumor agents; Cancer; Cell Line, Tumor; Cells, Cultured; Female; Gene Expression Regulation, Leukemic; Gene therapy; Gene transfer; Genetic Therapy - methods; Humanities and Social Sciences; Immunity; Immunity - genetics; Immunity - immunology; Immunostimulation; Immunosuppression; Immunotherapy; Immunotherapy, Adoptive - methods; Interferon; Interferons - genetics; Interferons - immunology; Interferons - metabolism; Leukemia; Lymphocytes; Lymphocytes T; Male; Mice, Inbred C57BL; Mice, Transgenic; Monocytes; multidisciplinary; Myeloid cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Priming; Science; Science (multidisciplinary); T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05315-0

Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing. An immune suppressive tumor microenvironment (TME) is a limitation for immunotherapy. Here the authors show that, in a B cell acute lymphoblastic leukemia mouse model, gene-based delivery of IFNα  reprograms the leukemia-induced immunosuppressive TME into immunostimulatory and enhances T-cell responses.