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Nat Commun. 2018 Jul 24;9(1):2896. doi: 10.1038/s41467-018-05315-0.

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

Author information

1
Vita-Salute San Raffaele University, 20132, Milan, Italy.
2
Targeted Cancer Gene Therapy Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
3
San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy.
4
Division of Immunology, Transplant and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
5
CUSSB-University Center for Statistics in the Biomedical Sciences, Vita-Salute San Raffaele University, 20132, Milan, Italy.
6
Centre for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.
7
San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. gentner.bernhard@hsr.it.
8
Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. gentner.bernhard@hsr.it.
9
Vita-Salute San Raffaele University, 20132, Milan, Italy. naldini.luigi@hsr.it.
10
Targeted Cancer Gene Therapy Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. naldini.luigi@hsr.it.
11
San Raffaele Telethon Institute for Gene Therapy, 20132, Milan, Italy. naldini.luigi@hsr.it.

Abstract

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.

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