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

Giulia Escobar, Luigi Barbarossa, Giulia Barbiera, Margherita Norelli, Marco Genua, Anna Ranghetti, Tiziana Plati, Barbara Camisa, Chiara Brombin, Davide Cittaro, Andrea Annoni, Attilio Bondanza, Renato Ostuni, Bernhard Gentner () and Luigi Naldini ()
Additional contact information
Giulia Escobar: Vita-Salute San Raffaele University
Luigi Barbarossa: IRCCS San Raffaele Scientific Institute
Giulia Barbiera: San Raffaele Telethon Institute for Gene Therapy
Margherita Norelli: Vita-Salute San Raffaele University
Marco Genua: San Raffaele Telethon Institute for Gene Therapy
Anna Ranghetti: IRCCS San Raffaele Scientific Institute
Tiziana Plati: San Raffaele Telethon Institute for Gene Therapy
Barbara Camisa: IRCCS San Raffaele Scientific Institute
Chiara Brombin: Vita-Salute San Raffaele University
Davide Cittaro: San Raffaele Telethon Institute for Gene Therapy
Andrea Annoni: San Raffaele Telethon Institute for Gene Therapy
Attilio Bondanza: Vita-Salute San Raffaele University
Renato Ostuni: San Raffaele Telethon Institute for Gene Therapy
Bernhard Gentner: San Raffaele Telethon Institute for Gene Therapy
Luigi Naldini: Vita-Salute San Raffaele University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05315-0

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