Huber Diana, Kors Tsima Abou, Schütt Lutz, Hofmann Linda, Betzler Annika, Lotfi Ramin, Oliveri Franziska, Schmid Sebastian, Wollenberg Barbara, Hoffmann Thomas K, Brunner Cornelia, Theodoraki Marie-Nicole
Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany.
Institute of Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessia, Ulm, Germany.
Br J Cancer. 2025 May 5. doi: 10.1038/s41416-025-03001-9.
Metastases are associated with poor survival in head and neck squamous cell carcinoma (HNSCC) patients and tumour-associated macrophages (TAMs) are important drivers in tumour progression and metastasis formation. Small extracellular vesicles (sEVs) are another important factor that contribute to systemic immunosuppression and pre-metastatic niche formation. Here, we investigate the effect of plasma sEVs from HNSCC patients on pre-metastatic niche formation, directly or through modulation of macrophages.
Primary macrophages were incubated with sEVs from plasma of HNSCC patients or healthy donors (HD). RNA profiles and inflammatory properties of macrophages were evaluated. Direct and indirect effects of sEVs on chemotaxis, T cell activation, proliferation and epithelial-to-mesenchymal transition (EMT) of tumour cells were investigated.
sEVs of HNSCC patients and HD induced different RNA profiles in macrophages. sEVs induced apoptosis and inhibition of T cell activation, while tumour cells were attracted by sEV-treated macrophages, but not sEVs directly. Proliferation was inhibited by both, sEVs and supernatant of EV-treated macrophages in HNSCC. Additionally, EMT in tumour cells was reversed by HNSCC sEV-treated macrophages.
sEVs from plasma of HNSCC patients transformed macrophages into metastasis-promoting TAMs and inhibited anti-tumour T cells, highlighting the potential of sEVs and TAMs as targets for therapeutic approaches.
转移与头颈部鳞状细胞癌（HNSCC）患者的不良生存相关，肿瘤相关巨噬细胞（TAM）是肿瘤进展和转移形成的重要驱动因素。小细胞外囊泡（sEV）是导致全身免疫抑制和前转移微环境形成的另一个重要因素。在此，我们研究HNSCC患者血浆sEV对前转移微环境形成的影响，直接影响或通过调节巨噬细胞来实现。
将原代巨噬细胞与HNSCC患者或健康供体（HD）血浆中的sEV一起孵育。评估巨噬细胞的RNA谱和炎症特性。研究sEV对肿瘤细胞趋化性、T细胞活化、增殖和上皮-间质转化（EMT）的直接和间接影响。
HNSCC患者和HD的sEV在巨噬细胞中诱导出不同的RNA谱。sEV诱导凋亡并抑制T细胞活化，而肿瘤细胞被sEV处理的巨噬细胞吸引，但不是被sEV直接吸引。HNSCC中，sEV和EV处理的巨噬细胞的上清液均抑制增殖。此外，HNSCC sEV处理的巨噬细胞逆转了肿瘤细胞中的EMT。
HNSCC患者血浆中的sEV将巨噬细胞转化为促进转移的TAM并抑制抗肿瘤T细胞，突出了sEV和TAM作为治疗靶点的潜力。
