Abstract 1920: XAGE1 cancer-testis antigen is a diagnostic and therapeutic target in lung adenocarcinomas

Abstract Introduction: Lung cancer is the leading cause of cancer deaths worldwide, and lung adenocarcinomas (LUAD) occupy approximately 50% among lung cancers. For LUAD, novel target therapies, immunotherapies, and ADCs have been extensively developed. TTF-1 has been widely used in pathological diagnosis of LUAD, although it is generally positive in normal alveolar and bronchial epithelial cells. There have never been LUAD-specific molecules and cancer antigens. On the other hand, we have reported that XAGE1 cancer-testis antigen expression is comparatively specific in LUAD and XAGE1 elicits spontaneous humoral and cellular immune responses in LUAD patients. Additionally, serum XAGE1 antibody (Ab) predicted clinical response to immune checkpoint therapy for non-small cell lung cancer (NSCLC), regardless of tumor PD-L1 status. Here, XAGE1 expression and serum XAGE1 Ab were examined in LUAD including adenosquamous carcinomas. Patients and Methods: We analyzed 415 (57% [415/727]) LUAD patients among 636 NSCLC and 91 small-cell lung cancer (SCLC) between 2015 and 2024 at Kawasaki Medical School Hospital. XAGE1 was stained in LUAD surgical specimens, using USO9-13 anti-XAGE1 Ab. The patients’ sera were obtained at diagnosis, and serum XAGE1 Ab was quantitatively measured by ELISA. The cutoff value of the positive Abs was defined as ≥ 100 titer. Results: XAGE1 Ab was detected in 20% (84/415) of overall LUAD patients, and 6% (8/134) of stage I, 15% (6/39) of II, 23% (16/69) of III, and 31% (53/169) of IV. XAGE1 protein was positive in 97 (42%) of 231 NSCLC surgical specimens, 93 (52%) of 179 LUAD, and 4 (8%) of 52 non-LUAD. Ninety-three (97%) of 97 XAGE1-positive NSCLC was LUAD, resulted in LUAD diagnostic accuracy of 52% sensitivity and 97% specificity. According to pathological stages of LUAD, XAGE1 protein was positive in 50% (61/123) of stage I, 50% (16/32) of II, and 64% (14/22) of III, regardless of driver gene status. Additionally, there were no differences in positive rates of XAGE1 cells across stages. Serum XAGE1 Ab was positive in 8% (5/61) of XAGE-positive stage I LUAD, 25% (4/16) of II, and 29% (4/14) of III. In analyses of tumor immune microenvironment, LUAD with XAGE1 protein and Ab showed abundant CD8 T-cell and few Treg infiltrations, conversely, LUAD without XAGE1 Ab did few CD8 T-cell and abundant Treg infiltrations. Conclusions: Our study demonstrated that XAGE1 protein was specifically expressed in approximately 50% or more of LUAD across disease stages but XAGE1 Ab was detected only in 10 to 30% of LUAD patients. Thus, XAGE1 is promising diagnostic marker in LUAD and novel therapeutic target especially in immunotherapy of LUAD. Citation Format: Mikio Oka, Koji Kurose, Yuji Nojima, Shinsuke Saisho, Katsuhiko Shimizu, Toru Oga, Masao Nakata. XAGE1 cancer-testis antigen is a diagnostic and therapeutic target in lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1920.