Armstrong Dominique, Chang Cheng-Yen, Hong Monica J, Green Linda, Shen Yichao, Hudson William, Mauk Kelsey E, Song Li-Zhen, Jammi Sheetal, Casal Benjamin, Burns Brianna, Creighton Chad J, Carisey Alexandre, Zhang Xiang H-F, McKenna Neil J, Kang Sung Wook, Lee Hyun-Sung, Decker William, Corry David B, Kheradmand Farrah
Translation Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Sci Adv. 2025 Feb 14;11(7):eads4227. doi: 10.1126/sciadv.ads4227. Epub 2025 Feb 12.
Adaptive immunity is critical in eliminating tumors, but cancer-intrinsic factors can subvert this function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in solid tumors and correlates with poor survival, but its role in tumorigenesis and antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of , a tumor suppressor, in human non-small cell lung cancers (NSCLC). Here, we show that constitutive expression of human with loss in mouse airway epithelia results in metastatic adenocarcinoma. Tumors showed distinct enrichment in IgA CD138 CXCR4 plasma cells (PCs) and increased expression of CXCL12 in endothelial cells. Consistently, human NSCLC expressing MAGE-A4 showed increased CD138 IgA PCs surrounding tumors. Abrogation of PCs decreased tumor burden, increased activated T cell infiltration, and reduced CD163CD206 macrophages in the MAGE-A4-induced lung tumors. These findings suggest MAGE-A4 promotes NSCLC tumorigenesis, in part, through the recruitment and retention of IgA PCs in the lungs.
适应性免疫在消除肿瘤方面至关重要，但肿瘤内在因素可破坏这一功能。黑色素瘤抗原A4（MAGE - A4）是一种癌 - 睾丸抗原，在实体瘤中表达，且与不良预后相关，但其在肿瘤发生和抗肿瘤免疫中的作用仍不清楚。我们发现，在人类非小细胞肺癌（NSCLC）中，MAGE - A4的表达与一种肿瘤抑制因子的缺失高度相关。在此，我们表明，在小鼠气道上皮细胞中，人类该因子缺失并组成性表达会导致转移性腺癌。肿瘤在IgA⁺CD138⁺CXCR4⁺浆细胞（PCs）中表现出明显富集，且内皮细胞中CXCL12的表达增加。同样，表达MAGE - A4的人类NSCLC显示肿瘤周围CD138⁺IgA⁺PCs增加。在MAGE - A4诱导的肺部肿瘤中，去除PCs可降低肿瘤负荷，增加活化T细胞浸润，并减少CD163⁺CD206⁺巨噬细胞。这些发现表明，MAGE - A4部分通过在肺部募集和保留IgA⁺PCs来促进NSCLC的肿瘤发生。
