Dataset Information

Inhibiting PI3 kinase-? in both myeloid and plasma cells remodels the suppressive tumor microenvironment in desmoplastic tumors.

ABSTRACT: Phosphoinositide-3-kinases (PI3Ks) are part of signal transducing enzymes that mediate key cellular functions in cancer and immunity. PI3K-? is crucial for cellular activation and migration in response to certain chemokines. PI3K-? is highly expressed in myeloid cells and promotes their migration and the production of inflammatory mediators. We found that PI3K-? was also highly expressed in tumor-associated B cells. IPI-549, the only PI3K-? inhibitor in clinical development, offers a unique approach to enhance the anti-tumor immune response. We encapsulated IPI-549 in targeted polymeric nanoparticles (NP) and tested its activity in both murine pancreatic cancer and melanoma models. IPI-549 NP significantly decreased tumor growth and prolonged host survival in both models. Importantly, IPI-549 NP treatment reduced the suppressive tumor microenvironment by decreasing both suppressive myeloid and plasma cells in the tumor. We concluded that IPI-549 NP delivery could be a promising method for treating pancreatic cancer and other immune-suppressive tumors.

SUBMITTER: Zhang X

PROVIDER: S-EPMC6815713 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Inhibiting PI3 kinase-γ in both myeloid and plasma cells remodels the suppressive tumor microenvironment in desmoplastic tumors.

Zhang Xueqiong X Shen Limei L Liu Qi Q Hou Lin L Huang Leaf L

Journal of controlled release : official journal of the Controlled Release Society 20190729

Phosphoinositide-3-kinases (PI3Ks) are part of signal transducing enzymes that mediate key cellular functions in cancer and immunity. PI3K-γ is crucial for cellular activation and migration in response to certain chemokines. PI3K-γ is highly expressed in myeloid cells and promotes their migration and the production of inflammatory mediators. We found that PI3K-γ was also highly expressed in tumor-associated B cells. IPI-549, the only PI3K-γ inhibitor in clinical development, offers a unique appr ...[more]

PMID: 31362079

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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-?), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-? (TGF-?), 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

Inhibiting PI3 kinase-? in both myeloid and plasma cells remodels the suppressive tumor microenvironment in desmoplastic tumors.

Publications

Inhibiting PI3 kinase-γ in both myeloid and plasma cells remodels the suppressive tumor microenvironment in desmoplastic tumors.

Similar Datasets

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