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

  • Sci Adv. 2025 Feb 14;11(7):eads4227. doi: 10.1126/sciadv.ads4227.
Dominique Armstrong  1  2 ,  Cheng-Yen Chang  1  2 ,  Monica J Hong  2 ,  Linda Green  3 ,  Yichao Shen  4  5 ,  William Hudson  4  5 ,  Kelsey E Mauk  2 ,  Li-Zhen Song  2 ,  Sheetal Jammi  2 ,  Benjamin Casal  2 ,  Brianna Burns  6 ,  Chad J Creighton  2  5 ,  Alexandre Carisey  7  8 ,  Xiang H-F Zhang  4  5 ,  Neil J McKenna  4 ,  Sung Wook Kang  5  9 ,  Hyun-Sung Lee  5  9 ,  William Decker  5  6 ,  David B Corry  1  2  5  6  10  11 ,  Farrah Kheradmand  1  2  5  6  10  11
Affiliations
  • 1. Translation Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3. Department of Pathology, Michael E. DeBakey VA, Houston, TX 77030, USA.
  • 4. Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 7. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 8. William T Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.
  • 9. Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
  • 10. Center for Translational Research in Inflammatory Diseases, Michael E. DeBakey VA, Houston, TX 77030, USA.
  • 11. Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA.
PMID: 39937892 DOI: 10.1126/sciadv.ads4227
Abstract

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.

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