Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression

Giulia Escobar, Davide Moi, Anna Ranghetti, Pinar Ozkal-Baydin, Mario Leonardo Squadrito, Anna Kajaste-Rudnitski, Attilio Bondanza, Bernhard Gentner, Michele De Palma, Roberta Mazzieri, Luigi Naldini

Research output: Contribution to journalArticle

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Abstract

The immunosuppressive tumor microenvironment represents a major hurdle to cancer therapy. We developed a gene transfer strategy into hematopoietic stem cells (HSCs) to target transgene expression to tumor-infiltrating monocytes/macrophages. Using a combination of transcriptional and microRNA-mediated control, we achieved selective expression of an interferon-α (IFN-α) transgene in differentiated monocytes of human hematochimeric mice. We show that IFN-α transgene expression does not impair engraftment and long-term multilineage repopulation of NSG (NOD/LtSz-scidIL2Rγnull) mice by transplanted human HSCs. By providing a source of human cytokines in the mice, we improved the functional reconstitution of human myeloid, natural killer, and T cell lineages, and achieved enhanced immune-mediated clearance of transplanted human breast tumors when hematopoiesis was engineered for tumor-targeted IFN-α expression. By applying our strategy to mouse breast cancer models, we achieved inhibition of tumor progression and experimental metastases in an autologous setting, likely through enhanced generation of effector T cells and their recruitment to the neoplastic tissues. By forcing IFN-α expression in tumor-infiltrating macrophages, we blunted their innate protumoral activity and reprogrammed the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity. Overall, our studies validate the feasibility, safety, and therapeutic potential of a new cancer gene therapy strategy, and open the way to test this approach as adjuvant therapy in advanced breast cancer patients.

Original languageEnglish
Article number217ra3
JournalScience Translational Medicine
Volume6
Issue number217
DOIs
Publication statusPublished - Jan 1 2014

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Genetic Engineering
Hematopoiesis
Interferons
Breast Neoplasms
Transgenes
Tumor Microenvironment
Neoplasms
Hematopoietic Stem Cells
Monocytes
Macrophages
Natural Killer T-Cells
Neoplasm Genes
Feasibility Studies
Cell Lineage
Immunosuppressive Agents
MicroRNAs
Genetic Therapy
Dendritic Cells
Therapeutics
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

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Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression. / Escobar, Giulia; Moi, Davide; Ranghetti, Anna; Ozkal-Baydin, Pinar; Squadrito, Mario Leonardo; Kajaste-Rudnitski, Anna; Bondanza, Attilio; Gentner, Bernhard; De Palma, Michele; Mazzieri, Roberta; Naldini, Luigi.

In: Science Translational Medicine, Vol. 6, No. 217, 217ra3, 01.01.2014.

Research output: Contribution to journalArticle

Escobar, Giulia ; Moi, Davide ; Ranghetti, Anna ; Ozkal-Baydin, Pinar ; Squadrito, Mario Leonardo ; Kajaste-Rudnitski, Anna ; Bondanza, Attilio ; Gentner, Bernhard ; De Palma, Michele ; Mazzieri, Roberta ; Naldini, Luigi. / Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression. In: Science Translational Medicine. 2014 ; Vol. 6, No. 217.
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