肿瘤细胞治疗研究
英文原题：Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression.
这些结果表明，NCL抑制通过一种依赖于直接抑制肿瘤基质的新作用机制，阻断了PDAC中淋系和髓系免疫抑制细胞的扩增，并促进了T细胞活化。
背景：胰腺导管腺癌（PDAC）微环境高度纤维化且缺氧，免疫细胞浸润较差。最近，我们发现核仁素（NCL）抑制可正常化肿瘤血管并损害PDAC生长。 方法：用选择性抑制NCL的拟肽N6L治疗具有免疫能力的小鼠PDAC模型。分析肿瘤浸润免疫细胞和肿瘤微环境的变化。 结果：N6L降低了调节性T细胞（Tregs）和髓源性抑制细胞（MDSCs）的比例，并增加了具有活化表型的肿瘤浸润T淋巴细胞（TILs）。低剂量抗VEGFR2治疗正常化了PDAC血管，但未调节免疫抑制微环境。对N6L治疗的PDAC肿瘤进行RNAseq分析显示，在体内和体外癌症相关成纤维细胞（CAF）扩增均减少。值得注意的是，N6L治疗降低了肿瘤组织和血清中的IL-6水平。用抗体阻断IL-6治疗mPDAC可降低Tregs和MDSCs的比例并增加TILs的数量，从而模拟N6L的作用。 结论：这些结果表明，NCL抑制阻断了淋巴和髓系免疫抑制细胞的扩增，并通过依赖于直接抑制肿瘤基质的新作用机制促进PDAC中的T细胞活化。
Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.
MEMBER ACCOUNT
登录成功会直接打开下一页。
