Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours
| Autor: | Aslan, Mansurov, Jun, Ishihara, Peyman, Hosseinchi, Lambert, Potin, Tiffany M, Marchell, Ako, Ishihara, John-Michael, Williford, Aaron T, Alpar, Michal M, Raczy, Laura T, Gray, Melody A, Swartz, Jeffrey A, Hubbell |
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| Rok vydání: | 2019 |
| Předmět: |
Inflammation
Mice Inbred BALB C Remission Induction Breast Neoplasms Adaptive Immunity Interleukin-12 Immunity Innate Tumor Burden Mice Inbred C57BL Disease Models Animal Epitopes Protein Domains Cell Line Tumor Neoplasms Tumor Microenvironment Animals Female Collagen Neoplasm Metastasis Melanoma Protein Binding |
| Zdroj: | Nature biomedical engineering. 4(5) |
| ISSN: | 2157-846X |
| Popis: | Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in 'immunologically cold' tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD-IL-12) in mice bearing aggressive mouse tumours, CBD-IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD-IL-12 induced sustained intratumoural levels of interferon-γ, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD-IL-12 potently synergized with CPI to eradicate large established melanomas, induced antigen-specific immunological memory and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD-IL-12 may potentiate CPI immunotherapy for immunologically cold tumours. |
| Databáze: | OpenAIRE |
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