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Nanoparticle-Mediated Trapping of Wnt Family Member 5A in Tumor Microenvironments Enhances Immunotherapy for B‑Raf Proto-Oncogene Mutant Melanoma
journal contribution
posted on 2018-01-25, 00:00 authored by Qi Liu, Hongda Zhu, Karthik Tiruthani, Limei Shen, Fengqian Chen, Keliang Gao, Xueqiong Zhang, Lin Hou, Degeng Wang, Rihe Liu, Leaf HuangDevelopment 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 ∼ 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.
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Keywords
immunogenic cell-death-mediated immunotherapylow-dose doxorubicin-induced immunogenic cell deathB-Raf proto-oncogene mutationTumor Microenvironments Enhances ImmunotherapyWnt 5a traptumor microenvironmenthost survival prolongationtumor growth inhibitionWnt 5a levelWnt family member 5trimeric trap proteinFizzled 7 receptorWnt Family Member 5Plasmid DNA encodingdendritic cell tolerancecationic lipid-protamine-DNA nanoparticlesBRAFWnt 5a
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