PTEN公司
癌症研究
肿瘤微环境
张力素
免疫检查点
黑色素瘤
抑癌基因
促炎细胞因子
前列腺癌
免疫系统
PI3K/AKT/mTOR通路
生物
医学
癌症
免疫疗法
癌变
免疫学
炎症
细胞生物学
信号转导
肿瘤细胞
遗传学
作者
Yao‐Xin Lin,Yi Wang,Jianxun Ding,Aiping Jiang,Jie Wang,Mian Yu,Sara Blake,Shuaishuai Liu,Charles J. Bieberich,Omid C. Farokhzad,Lin Mei,Hao Wang,Jinjun Shi
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-06-23
卷期号:13 (599)
被引量:93
标识
DOI:10.1126/scitranslmed.aba9772
摘要
Increasing clinical evidence has demonstrated that the deletion or mutation of tumor suppressor genes such as the gene-encoding phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in cancer cells may correlate with an immunosuppressive tumor microenvironment (TME) and poor response or resistance to immune checkpoint blockade (ICB) therapy. It is largely unknown whether the restoration of functional PTEN may modulate the TME and improve the tumor's sensitivity to ICB therapy. Here, we demonstrate that mRNA delivery by polymeric nanoparticles can effectively induce expression of PTEN in Pten-mutated melanoma cells and Pten-null prostate cancer cells, which in turn induces autophagy and triggers cell death-associated immune activation via release of damage-associated molecular patterns. In vivo results illustrated that PTEN mRNA nanoparticles can reverse the immunosuppressive TME by promoting CD8+ T cell infiltration of the tumor tissue, enhancing the expression of proinflammatory cytokines, such as interleukin-12, tumor necrosis factor-α, and interferon-γ, and reducing regulatory T cells and myeloid-derived suppressor cells. The combination of PTEN mRNA nanoparticles with an immune checkpoint inhibitor, anti-programmed death-1 antibody, results in a highly potent antitumor effect in a subcutaneous model of Pten-mutated melanoma and an orthotopic model of Pten-null prostate cancer. Moreover, the combinatorial treatment elicits immunological memory in the Pten-null prostate cancer model.
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