Ponzo Matteo, Debesset Anais, Cossutta Mélissande, Chalabi-Dchar Mounira, Houppe Claire, Pilon Caroline, Nicolas-Boluda Alba, Meunier Sylvain, Raineri Fabio, Thiolat Allan, Nicolle Rémy, Maione Federica, Brundu Serena, Cojocaru Carina Florina, Bouvet Philippe, Bousquet Corinne, Gazeau Florence, Tournigand Christophe, Courty José, Giraudo Enrico, Cohen José L, Cascone Ilaria
Immune Regulation and Biotherapy, Inserm U955, IMRB University of Paris-Est Creteil (UPEC) 8, INSERM, IMRB, F-94010 Créteil, France.
Cancer Research Center of Lyon, Cancer Cell Plasticity Department, University of Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, F-69008 Lyon, France.
Cancers (Basel). 2022 Aug 31;14(17):4265. doi: 10.3390/cancers14174265.
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.
胰腺导管腺癌（PDAC）的微环境具有高度纤维化和缺氧的特点，免疫细胞浸润较差。最近，我们发现抑制核仁素（NCL）可使肿瘤血管正常化并抑制PDAC生长。方法：用选择性抑制NCL的假肽N6L治疗具有免疫活性的PDAC小鼠模型。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性T淋巴细胞（TILs）。低剂量抗VEGFR2治疗使PDAC血管正常化，但未调节免疫抑制微环境。对N6L治疗的PDAC肿瘤进行RNAseq分析发现，体内和体外癌相关成纤维细胞（CAF）的扩增均减少。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。用阻断IL-6的抗体治疗mPDAC可降低Tregs和MDSCs的比例，并增加TILs的数量，从而模拟了N6L的作用。结论：这些结果表明，抑制NCL可通过一种依赖于直接抑制肿瘤基质的新作用机制，阻断淋巴样和髓样免疫抑制细胞的扩增，并促进PDAC中的T细胞活化。
