Fang Qi, Chen Xiao, Cao Fei, Xu Pengfei, Zhao Zheng, Lin Roubin, Wu Di, Deng Wuguo, Liu Xuekui
Department of Head and Neck Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, Guangdong, People's Republic of China.
State Key Laboratory of Oncology in South China, 651 Dongfeng East Road, Guangzhou 510060, Guangdong, People's Republic of China.
Theranostics. 2024 Oct 28;14(18):7199-7218. doi: 10.7150/thno.102390. eCollection 2024.
Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy against head and neck squamous cell carcinoma (HNSCC), but their overall response rate (ORR) remains limited. Previous studies have highlighted the crucial role of sphingosine kinases (SPHKs) in the tumor microenvironment (TME); however, their function in immunotherapy remains unclear. We conducted comprehensive bioinformatics analysis, functional studies, and clinical validation, to investigate the role of SPHK1 in the immunology of HNSCC. Functionally, SPHK1 significantly promoted tumor growth by inhibiting anti-tumor immunity in immune-competent HNSCC mouse models and tumor-T cell co-cultures. Mechanistic analysis revealed that SPHK1 regulated matrix metalloproteinase-1 (MMP1) expression via the MAPK1 pathway, which subsequently influenced tumor programmed cell death ligand 1 (PD-L1) expression. Furthermore, SPHK1 and MMP1 could predict the efficacy of programmed cell death 1 monoclonal antibody (PD-1 mAb) immunotherapy in HNSCC and were independent risk factors for survival in patients with HNSCC. Our study reveals a novel role for SPHK1 in mediating immune evasion in HNSCC through the regulation of the MMP1-PD-L1 axis. We identified SPHK1 and MMP1 as predictive biomarkers for the therapeutic response to PD-1 mAb and provided new therapeutic targets for patients with HNSCC.
免疫检查点抑制剂（ICIs）已显示出对头颈鳞状细胞癌（HNSCC）具有显著疗效，但其总体缓解率（ORR）仍然有限。先前的研究强调了鞘氨醇激酶（SPHKs）在肿瘤微环境（TME）中的关键作用；然而，它们在免疫治疗中的功能仍不清楚。我们进行了全面的生物信息学分析、功能研究和临床验证，以研究SPHK1在HNSCC免疫中的作用。在功能上，在具有免疫活性的HNSCC小鼠模型和肿瘤-T细胞共培养中，SPHK1通过抑制抗肿瘤免疫显著促进肿瘤生长。机制分析表明，SPHK1通过MAPK1途径调节基质金属蛋白酶-1（MMP1）的表达，随后影响肿瘤程序性细胞死亡配体1（PD-L1）的表达。此外，SPHK1和MMP1可以预测程序性细胞死亡1单克隆抗体（PD-1 mAb）免疫治疗在HNSCC中的疗效，并且是HNSCC患者生存的独立危险因素。我们的研究揭示了SPHK1在通过调节MMP1-PD-L1轴介导HNSCC免疫逃逸中的新作用。我们将SPHK1和MMP1鉴定为对PD-1 mAb治疗反应的预测生物标志物，并为HNSCC患者提供了新的治疗靶点。
