文章：

Axl调控NK细胞活性在头颈癌中形成免疫抑制性肿瘤免疫微环境

Axl Regulation of NK Cell Activity Creates an Immunosuppressive Tumor Immune Microenvironment in Head and Neck Cancer

原文发布日期：15 March 2025

DOI: 10.3390/cancers17060994

类型: Article

开放获取: 是

英文摘要：

Background: Head and neck cancer (HNC) evades immune responses by manipulating the tumor immune microenvironment (TIME). Tumor-bound Axl has been implicated in promoting an immunosuppressive TIME in HNC, though its precise role remains unclear. Understanding Axl’s contribution to immune evasion in HNC could lead to the identification of new therapeutic targets; therapies directed at these targets could be combined with and thereby enhance immunotherapies.Results:Using Axl knockout (Axl KO) cell lines derived from the immunologically “cold” MOC2 mouse model, we found that Axl loss delayed tumor growth in immunocompetent mice. This was accompanied by reduced immunosuppressive cells, including MDSCs, Tregs, B cells, and neutrophils, and increased infiltration of cytotoxic CD8 T cells and NK cells. To identify the immune population(s) responsible for these changes, Axl KO tumors were implanted in immune-deficient mice. Axl KO tumor growth in athymic nude mice (which lack T cells) was unchanged, whereas tumor growth in NCG mice (which lack NK cells) was rescued, suggesting that NK cells mediate the Axl KO tumor growth delay. Further, Axl loss enhanced NK cell cytotoxicity in vitro and in vivo, and NK cell depletion reversed delayed Axl KO tumor growth. Mechanistically, Axl KO tumors showed decreased expression of CD73 and CCL2, which inhibit NK cells, and increased expression of CCL5 and CXCL10, which promote NK cell recruitment and activation.Conclusions:These novel findings suggest that tumor-bound Axl fosters an immunosuppressive TIME by inhibiting NK cell recruitment and function, thereby promoting tumor growth. Targeting Axl may enhance NK cell-mediated tumor killing and improve immunotherapy efficacy in HNC.

摘要翻译： 

背景：头颈癌通过调控肿瘤免疫微环境来逃避免疫应答。肿瘤结合的Axl蛋白被认为在头颈癌中促进免疫抑制性肿瘤微环境的形成，但其确切作用机制尚不明确。阐明Axl在头颈癌免疫逃逸中的作用有助于发现新的治疗靶点；针对这些靶点的治疗可与免疫疗法联合应用，从而增强治疗效果。 结果：利用免疫"冷"肿瘤MOC2小鼠模型构建的Axl敲除细胞系，我们发现Axl缺失可延缓免疫健全小鼠的肿瘤生长。这一现象伴随着免疫抑制细胞（包括MDSCs、Tregs、B细胞和中性粒细胞）的减少，以及细胞毒性CD8 T细胞和NK细胞浸润的增加。为明确导致这些变化的免疫细胞群体，我们将Axl敲除肿瘤植入免疫缺陷小鼠。在缺乏T细胞的无胸腺裸鼠中，Axl敲除肿瘤的生长未受影响；而在缺乏NK细胞的NCG小鼠中，肿瘤生长得到恢复，这表明NK细胞介导了Axl敲除导致的肿瘤生长延迟。进一步研究发现，Axl缺失在体外和体内均能增强NK细胞的细胞毒性，且清除NK细胞可逆转Axl敲除肿瘤的生长延迟。机制研究表明，Axl敲除肿瘤中抑制NK细胞的CD73和CCL2表达降低，而促进NK细胞募集与活化的CCL5和CXCL10表达增加。 结论：这些新发现表明，肿瘤结合的Axl通过抑制NK细胞的募集与功能来促进免疫抑制性肿瘤微环境的形成，从而推动肿瘤生长。靶向Axl可能增强NK细胞介导的肿瘤杀伤作用，提高头颈癌免疫治疗的疗效。

原文链接：

Axl Regulation of NK Cell Activity Creates an Immunosuppressive Tumor Immune Microenvironment in Head and Neck Cancer