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 and Naldini, Luigi (2014) Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression. Science Translational Medicine, 6 217: . doi:10.1126/scitranslmed.3006353

Author 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
Title Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression
Journal name Science Translational Medicine   Check publisher's open access policy
ISSN 1946-6234
Publication date 2014-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1126/scitranslmed.3006353
Open Access Status
Volume 6
Issue 217
Total pages 13
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Collection year 2015
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article # 217ra3

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
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UQ Diamantina Institute Publications
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