PI3Kgamma Inhibitor Attenuates Immunosuppressive Effect of Poly(l-Glutamic Acid)-Combretastatin A4 Conjugate in Metastatic Breast Cancer

Advanced Science
Hanjiao QinXuesi Chen

Abstract

Vascular disrupting agents (VDAs) have great potential for cancer treatment. Poly(l-glutamic acid)-combretastatin A4 conjugate (PLG-CA4) is a novel class of VDAs. Though it has notable antitumor activity, it can induce host immune responses that promote tumor growth. Here, PLG-CA4 induces the polarization of tumor-associated macrophages (TAMs) toward the M2-like phenotype in 4T1 metastatic breast cancer (Control 30% vs PLG-CA4 53%; p < 0.05). Compared to the monotherapy of PLG-CA4, inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) attenuates the immunosuppressive effect of PLG-CA4 treatment by decreasing the number of M2-like TAMs (2.0 × 104 to 1.5 × 104 per tumor) and potential enhancement of cytotoxic T lymphocyte (3.0 × 104 to 5.7 × 104 per tumor). Importantly, PI3Kγ inhibitor synergizing with PLG-CA4 significantly extends the mean survival time from 52 days in monotherapy-treated mice to 61.8 days. Additionally, the combination of PLG-CA4 and PI3Kγ inhibitor improves the tumor therapeutic effect of NLG919, an inhibitor of immune checkpoint indoleamine 2,3-dioxygenase (IDO). As far as it is known, this is the first demonstrated study that VDAs induce the reshaping of macrophages to the M2-like phenotype. The findings als...Continue Reading

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Citations

Jul 31, 2020·Biomolecules·Paulina PecynaMalgorzata Kucinska
May 24, 2020·Annals of the New York Academy of Sciences·Martha Lopez-YrigoyenJeffrey W Pollard
Apr 22, 2020·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yang ZhouHuile Gao
Oct 13, 2020·Macromolecular Bioscience·Haiyang YuZhaohui Tang
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Nov 3, 2020·Advanced Drug Delivery Reviews·Chao DengZhiyuan Zhong
Mar 11, 2021·International Journal of Nanomedicine·Zhongmin LiZhenbo Shu
Jan 23, 2021·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Duoyi ZhaoXuesi Chen
May 1, 2021·Advanced Healthcare Materials·Yu ZhangXuesi Chen
Aug 28, 2021·Cancers·Giovanni Nicolao BertaBarbara Mognetti

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Methods Mentioned

BETA
flow cytometry

Software Mentioned

GraphPad
Treestar
FlowJo
Image J
ImageJ
GraphPad Prism

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