Nanoparticle-Mediated Trapping of Wnt Family Member 5A in Tumor Microenvironments Enhances Immunotherapy for B-Raf Proto-Oncogene Mutant Melanoma.
ACS Nano
; 12(2): 1250-1261, 2018 02 27.
Article
em En
| MEDLINE
| ID: mdl-29370526
ABSTRACT
Development of an effective treatment against advanced tumors remains a major challenge for cancer immunotherapy. Approximately 50% of human melanoma is driven by B-Raf proto-oncogene mutation (BRAF mutant). Tumors with such mutation are desmoplastic, highly immunosuppressive, and often resistant to immune checkpoint therapies. We have shown that immunotherapy mediated by low-dose doxorubicin-induced immunogenic cell death was only partially effective for this type of tumor and not effective in long-term inhibition of tumor progression. Wnt family member 5A (Wnt5a), a signaling protein highly produced by BRAF mutant melanoma cells, has been implicated in inducing dendritic cell tolerance and tumor fibrosis, thus hindering effective antigen presentation and T-cell infiltration. We hypothesized that Wnt5a is a key molecule controlling the immunosuppressive tumor microenvironment in metastatic melanoma. Accordingly, we have designed and generated a trimeric trap protein, containing the extracellular domain of Fizzled 7 receptor that binds Wnt5a with a Kd â¼ 278 nM. Plasmid DNA encoding for the Wnt5a trap was delivered to the tumor by using cationic lipid-protamine-DNA nanoparticles. Expression of Wnt5a trap in the tumor, although transient, was greater than that of any other major organs including liver, resulting in a significant reduction of the Wnt5a level in the tumor microenvironment without systematic toxicity. Significantly, combination of Wnt5a trapping and low-dose doxorubicin showed great tumor growth inhibition and host survival prolongation. Our findings indicated that efficient local Wnt5a trapping significantly remodeled the immunosuppressive tumor microenvironment to facilitate immunogenic cell-death-mediated immunotherapy.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doxorrubicina
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Proteínas Proto-Oncogênicas B-raf
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Nanopartículas
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Microambiente Tumoral
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Proteína Wnt-5a
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Melanoma
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Antibióticos Antineoplásicos
Limite:
Animals
Idioma:
En
Revista:
ACS Nano
Ano de publicação:
2018
Tipo de documento:
Article