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

Journal of Controlled Release : Official Journal of the Controlled Release Society
Xueqiong ZhangLeaf Huang

Abstract

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 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.

Citations

Apr 18, 2020·Journal of Experimental & Clinical Cancer Research : CR·Shiming TanQianjin Liao
Feb 11, 2021·Cells·Seiji MabuchiNaoko Komura
Feb 12, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Jaehyun KimYong-Hee Kim
Jun 18, 2021·Nano-micro Letters·Qinjun ChenChen Jiang
Jul 13, 2021·Signal Transduction and Targeted Therapy·Huakan ZhaoYongsheng Li
Jul 10, 2021·Cellular & Molecular Immunology·Bradley I ReinfeldJeffrey C Rathmell
Aug 29, 2021·Journal for Immunotherapy of Cancer·David G DeNardoJohanna Bendell

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