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

IF 4.5 2区 医学 Q1 ONCOLOGY
Cancers Pub Date : 2025-03-15 DOI:10.3390/cancers17060994
Kourtney L Kostecki, Regan L Harmon, Mari Iida, Madelyn A Harris, Bridget E Crossman, Justine Yang Bruce, Ravi Salgia, Deric L Wheeler
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Abstract

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.

背景:头颈癌(HNC)通过操纵肿瘤免疫微环境(TIME)来逃避免疫反应。与肿瘤结合的Axl与促进HNC免疫抑制性TIME有关,但其确切作用仍不清楚。了解Axl在HNC免疫逃避中的作用可帮助确定新的治疗靶点;针对这些靶点的疗法可与免疫疗法相结合,从而增强免疫疗法的效果。研究结果利用从免疫 "冷 "MOC2小鼠模型中提取的Axl基因敲除(Axl KO)细胞系,我们发现Axl缺失会延缓免疫功能正常小鼠的肿瘤生长。与此同时,包括MDSCs、Tregs、B细胞和中性粒细胞在内的免疫抑制细胞减少,细胞毒性CD8 T细胞和NK细胞浸润增加。为了确定导致这些变化的免疫群体,Axl KO肿瘤被植入免疫缺陷小鼠体内。Axl KO肿瘤在无胸腺裸鼠(缺乏T细胞)中的生长没有变化,而在NCG小鼠(缺乏NK细胞)中的生长得到了挽救,这表明NK细胞介导了Axl KO肿瘤生长的延迟。此外,Axl缺失增强了体外和体内NK细胞的细胞毒性,NK细胞耗竭逆转了Axl KO肿瘤生长延迟。从机理上讲,Axl KO肿瘤显示抑制NK细胞的CD73和CCL2表达减少,而促进NK细胞募集和激活的CCL5和CXCL10表达增加。结论这些新发现表明,与肿瘤结合的Axl通过抑制NK细胞的募集和功能促进免疫抑制TIME,从而促进肿瘤生长。靶向 Axl 可增强 NK 细胞介导的肿瘤杀伤力,提高 HNC 免疫疗法的疗效。
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来源期刊
Cancers
Cancers Medicine-Oncology
CiteScore
8.00
自引率
9.60%
发文量
5371
审稿时长
18.07 days
期刊介绍: Cancers (ISSN 2072-6694) is an international, peer-reviewed open access journal on oncology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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