Remodeling tumor immune microenvironment via targeted blockade of PI3K-γ and CSF-1/CSF-1R pathways in tumor associated macrophages for pancreatic cancer therapy.

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ID: 93150
2020
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Abstract
Immunotherapy has exhibited great potential in cancer treatment. However, for immunosuppressive tumors such as pancreatic cancer, immunotherapy is far from satisfactory. PI3K-γ and colony stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) pathways are involved in the infiltration and polarization of immunosuppressive cells including M2 tumor associated macrophages (M2 TAMs), causing a suppressive tumor immune microenvironment (TIME) in pancreatic cancer. Herein, a M2 TAM targeting nanomicelle was developed to co-deliver PI3K-γ inhibitor NVP-BEZ 235 and CSF-1R-siRNA for specific TAMs reprogramming and antitumor immune responses activation. M2 TAM targeting peptide M2pep was modified on a mixed micelle, which was potent to co-encapsulate BEZ 235 and CSF-1R siRNA. The formulated nanomicelle increased M2 TAM targeting efficiency both in vitro and in vivo. Compared with single pathway blockade, dual blockade of PI3k-γ and CSF-1R demonstrated enhanced TAM remodeling effects by reducing M2 TAM level and elevating M1 TAM level, and also suppressed tumor infiltration of myeloid-derived suppressor cells (MDSCs). Consequently, the M2 TAM targeting reprogramming system activated antitumor immune responses and achieved enhanced anti-pancreatic tumor effects via PI3K-γ blockade and downregulation of CSF-1R. The M2pep modified nanomicelle provides a promising method for co-delivery of siRNA and small molecule inhibitor to M2 TAM. Dual inhibition of both PI3K-γ and CSF-1R can remodel TIME and activate antitumor immune responses synergistically, providing an alternative approach for pancreatic cancer treatment.
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Authors Li, Man;Li, Mengmeng;Yang, Yiliang;Liu, Yingke;Xie, Hanbing;Yu, Qianwen;Tian, Lifeng;Tang, Xian;Ren, Kebai;Li, Jianping;Zhang, Zhirong;He, Qin;
Journal Journal of controlled release : official journal of the Controlled Release Society
Year 2020
DOI
S0168-3659(20)30087-0
URL
Keywords
Pancreatic cancer immunotherapy csf-1r m2 tam pi3k-γ

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