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Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.

ABSTRACT: The off-target distribution of anticancer nanoparticles to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this nanoparticle detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate approximately 70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Furthermore, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well known to be a major barrier to the delivery of therapeutic nanoparticles. Collectively, our results offer a proof of concept for the use of nanoparticles to modify TAFs as an effective strategy to treat desmoplastic cancers. Cancer Res; 77(3); 719-31. ©2016 AACR.

SUBMITTER: Miao L

PROVIDER: S-EPMC5290135 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.

Miao Lei L Liu Qi Q Lin C Michael CM Luo Cong C Wang Yuhua Y Liu Lina L Yin Weiyan W Hu Shihao S Kim William Y WY Huang Leaf L

Cancer research 20161118 3

The off-target distribution of anticancer nanoparticles to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this nanoparticle detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes and administered ...[more]

PMID: 27864344

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Project description:Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of desmoplastic melanoma. Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis. Immune cell populations in tumor and LNs were detected by flow cytometry. Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells. A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME. In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced. Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped. Therefore, a tumor-specific peptide vaccine was combined with Frax NEs. The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death. Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced desmoplastic melanoma.

Dataset Information

Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.

Publications

Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.

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