Yang Zeyang, Wang Xuanyin, Zhu Xu, Li Long, Zeng Xianling, Ren Jiaming, Wang Lu, Wu Jiangwei, Zhang Qiaoling, Wang Siyu, Lu Maoqin, Zhai Juan, Liu Xinlei, Xiao Jing, Jin Tao, Zhang Ying, Wang Yun, Zhang Jian, Zeng Zhu, Wu Jieheng
Department of Immunology, Guizhou Medical University, Guiyang, China.
Department of Thoracic Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Front Cell Dev Biol. 2025 Jul 15;13:1635915. doi: 10.3389/fcell.2025.1635915. eCollection 2025.
Tumor immune escape is a critical step in tumor progression. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) express abundant PD-L1 and suppress the functions of CD8T cells, enablingd immune escape. CD248 is a candidate bioindicator for CAFs associated with non-small cell lung cancer (NSCLC), although its involvement in immune escape is not known.
Fibroblasts were isolated from tumor and normal lung tissues from patients. We detected the expression of CD248 and PD-L1 on CAFs. Then, the influence of CAFs inhibited the function of CD8T cells promoting NSCLC immune escape was assessed and . Finally, explored the mechanisms of which CD248 induced PD-L1 expression on CAFs.
Herein, we demonstrated that CD248 increased CAF PD-L1 levels, inhibiting CD8T-cell function, thereby promoting NSCLC cell invasion and migration. CD248-induced FAK/Src/JNK/c-Jun axis activation promoted PD-L1 expression on CAFs. In tumor-bearing mice, lung tumors grew significantly slower, and the amount of granzyme BCD8T cells was greater in fibroblast-specific CD248 gene knockout mice than in wild-type mice. More importantly, we found that tislelizumab efficiency was improved in CD248 gene knockout mice.
Our findings demonstrate that CD248 activates FAK/Src/JNK/c-Jun, thereby inducing PD-L1 expression on CAFs, which promotes NSCLC immune escape.
肿瘤免疫逃逸是肿瘤进展的关键步骤。肿瘤微环境（TME）中的癌症相关成纤维细胞（CAF）表达大量程序性死亡配体1（PD-L1）并抑制CD8 + T细胞功能，从而导致免疫逃逸。CD248是与非小细胞肺癌（NSCLC）相关的CAF的候选生物标志物，但其在免疫逃逸中的作用尚不清楚。
从患者的肿瘤和正常肺组织中分离成纤维细胞。我们检测了CAF上CD248和PD-L1的表达。然后，评估CAF对促进NSCLC免疫逃逸的CD8 + T细胞功能的抑制作用。最后，探讨CD248诱导CAF上PD-L1表达的机制。
在此，我们证明CD248增加了CAF的PD-L1水平，抑制了CD8 + T细胞功能，从而促进了NSCLC细胞的侵袭和迁移。CD248诱导的黏着斑激酶（FAK）/Src/应激活化蛋白激酶（JNK）/c-Jun轴激活促进了CAF上PD-L1的表达。在荷瘤小鼠中，成纤维细胞特异性CD248基因敲除小鼠的肺肿瘤生长明显较慢，颗粒酶B + CD8 + T细胞数量比野生型小鼠更多。更重要的是，我们发现替雷利珠单抗在CD248基因敲除小鼠中的疗效得到了改善。
我们的研究结果表明，CD248激活FAK/Src/JNK/c-Jun，从而诱导CAF上PD-L1的表达，促进NSCLC免疫逃逸。
