MAGE-A4 induces non-small cell lung cancer and tumor-promoting plasma cell accumulation

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 PTEN, a tumor suppressor, in human non-small cell lung cancers (NSCLC). Here, we show that constitutive expression of human MAGE-A4 with Pten 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 CD163⁺CD206⁺ 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.