Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models

Autor: Filippo Birocchi, Melania Cusimano, Federico Rossari, Stefano Beretta, Paola M. V. Rancoita, Anna Ranghetti, Stefano Colombo, Barbara Costa, Peter Angel, Francesca Sanvito, Marcella Callea, Rossana Norata, Linda Chaabane, Tamara Canu, Antonello Spinelli, Marco Genua, Renato Ostuni, Ivan Merelli, Nadia Coltella, Luigi Naldini
Rok vydání: 2022
Předmět:
Zdroj: Science Translational Medicine. 14
ISSN: 1946-6242
1946-6234
Popis: Glioblastoma multiforme (GBM) is the most common and lethal brain tumor characterized by a strongly immunosuppressive tumor microenvironment (TME) that represents a barrier also for the development of effective immunotherapies. The possibility to revert this hostile TME by immunoactivating cytokines is hampered by the severe toxicity associated with their systemic administration. Here, we exploited a lentiviral vector–based platform to engineer hematopoietic stem cells ex vivo with the aim of releasing, via their tumor-infiltrating monocyte/macrophage progeny, interferon-α (IFN-α) or interleukin-12 (IL-12) at the tumor site with spatial and temporal selectivity. Taking advantage of a syngeneic GBM mouse model, we showed that inducible release of IFN-α within the TME achieved robust tumor inhibition up to eradication and outperformed systemic treatment with the recombinant protein in terms of efficacy, tolerability, and specificity. Single-cell RNA sequencing of the tumor immune infiltrate revealed reprogramming of the immune microenvironment toward a proinflammatory and antitumoral state associated with loss of a macrophage subpopulation shown to be associated with poor prognosis in human GBM. The spatial and temporal control of IL-12 release was critical to overcome an otherwise lethal hematopoietic toxicity while allowing to fully exploit its antitumor activity. Overall, our findings demonstrate a potential therapeutic approach for GBM and set the bases for a recently launched first-in-human clinical trial in patients with GBM.
Databáze: OpenAIRE
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