Nat Commun:武汉大学等多单位合作!钟波/林丹丹/褚倩揭示非小细胞肺癌新的潜在的治疗靶标

2020-12-31 枫叶 iNature

肺癌是最普遍的癌症,也是与癌症相关的死亡的主要原因,每年在全球造成200万以上的新诊断和170万死亡。大约85%的被诊断肺癌是非小细胞肺癌(NSCLC),其中50%以上的腺癌和30%的鳞状癌。免疫检查

肺癌是最普遍的癌症,也是与癌症相关的死亡的主要原因,每年在全球造成200万以上的新诊断和170万死亡。大约85%的被诊断肺癌是非小细胞肺癌(NSCLC),其中50%以上的腺癌和30%的鳞状癌。免疫检查点疗法对非小细胞肺癌(NSCLC)的疗效在很大程度上取决于肿瘤微环境(TME)。

武汉大学钟波,林丹丹及华中科技大学褚倩共同通讯在Nature Communications 在线发表题为“CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer”的研究论文,该研究证明了CCL7通过募集常规DC 1(cDC1)促进KrasLSL-G12D / + Tp53fl / fl(KP)和KrasLSL-G12D / + Lkb1fl / fl(KL)NSCLC小鼠模型的抗PD-1治疗,促进T细胞扩增。 

CCL7在NSCLC肿瘤组织中表现出高表达,并与TME中cDC1的浸润和NSCLC患者的整体生存呈正相关。CCL7缺乏会损害cDC1在TME中的浸润以及随后在支气管引流淋巴结和TME中CD8 +和CD4 + T细胞的扩增,从而促进KP小鼠模型中的肿瘤发展。单独或与抗PD-1组合使用CCL7进入肺部可显著抑制肿瘤的发展,并延长KP和KL小鼠的生存期。这些发现表明,CCL7可能作为非小细胞肺癌检查点免疫疗法的生物标志物和佐剂。

已经开发出各种小分子抑制剂和单克隆抗体来靶向这些遗传改变并显著改善NSCLC患者的预后。尽管取得了这些进展,但目前尚无针对KRAS突变(G12C,G12V或G12D)的NSCLC患者的具体治疗策略,KRAS是10%至20%的NSCLC发病率中最常见的致癌驱动因素。此外,在KRAS突变的NSCLC中已鉴定出常见的共突变伴侣,包括TP53,LKB1和CDKN2A。这些共突变因子提供了不同的基因表达谱,并可能为KRAS突变的NSCLC确定不同的治疗策略。已经开发出表达突变的KrasG12D并同时使Tp53(KrasLSL-G12D / + Tp53fl / fl; KP)或Lkb1(KrasLSL-G12D / + Lkb1fl / fl; KL)失活的小鼠模型,并提供了强大的工具来进行筛查和评估KRAS突变的NSCLCs的有效疗法。

最近,采用免疫检查点阻滞剂的检查点免疫疗法,例如抗程序性死亡1(anti-PD-1)和抗程序性死亡配体1(anti-PD-L1)抗体已显著改善了无进展生存期(PFS)。但是,即使在PD-L1阳性水平较高的NSCLC患者中,客观缓解率(ORR)约为45%,这可能是由于肿瘤浸润性白细胞的进入或增殖缺陷或被TME中的其他分子途径抑制。

趋化因子配体7(CCL7,也称为MCP-3)是首先从MG-63骨肉瘤细胞的培养上清中表征的单核细胞的趋化因子和强力引诱剂。CCL7在内皮细胞,成纤维细胞和单核细胞中低水平表达,并受各种刺激(包括病毒,I型或II型干扰素(IFN))上调。然而,据报道,在外源小鼠模型中,肿瘤细胞中CCL7的过表达通过促进肿瘤细胞的增殖和转移来促进肿瘤发生,或通过将免疫细胞募集到肿瘤中来保持肿瘤的生长。目前尚不清楚CCL7是否以及如何参与体内原发性NSCLC的发展。

在这里,该研究显示NSCLC肿瘤活检中CCL7的高表达与NSCLC患者的OS正相关。CCL7缺乏会促进KP小鼠模型中NSCLC的发育。从机制上讲,CCL7促进cDC1趋向TME,从而促进T细胞扩增和抗肿瘤免疫。一致地,与单独的抗PD-1治疗相比,CCL7和抗PD-1治疗的组合显著抑制了肿瘤发生并延长了KP或KL小鼠的存活。这些发现共同表明,CCL7可作为佐剂,通过调节TME促进NSCLC的检查点免疫治疗。

原始出处:

Man Zhang, Wei Yang, Peng Wang,et al.CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer. Nat Commun. 2020 Nov 30;11(1):6119. doi: 10.1038/s41467-020-19973-6.

 

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    2021-09-17 liuli5079
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    2021-03-28 liye789132251
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    2021-01-02 zhaojie88
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    2021-01-01 ms6000001700483633

    已学习

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