Clinical Significance of Humoral Immunity Against XAGE1 Cancer-Testis Antigen in Lung Adenocarcinoma.

162 Background: Cancer-testis antigens (CTAs) are expressed predominantly in the testis and various types of cancer. Some of CTAs are highly immunogenic and attractive targets for cancer immunotherapy. We identified XAGE1 as a dominant CTA in lung adenocarcinoma (LAD). In this study, we examined immune responses to XAGE1 and the clinical significance in LAD patients. Methods: Expression of XAGE1 and immune checkpoint molecules in LAD tissues was determined by immunohistochemistry. The XAGE1 antibody and T cell immune responses were analyzed in blood samples. Then, overall survival (OS) of the XAGE1 antigen-positive and -negative, and XAGE1 antibody-positive and -negative patients was analyzed. Results: The XAGE1 antigen was expressed in approximately 40% of LAD, and the expression reflected shortened OS of pStage I-IIIA LAD in two japanese cohorts. In addition, expression profiles of XAGE1 and immune checkpoint molecules of PD-L1 and galectin-9 on tumor cells efficiently predicted OS of pStage I-IIIA LAD patients. The XAGE1 antibody response was observed in 6% (9/155) of our pStage I-IIIA, and 20% (34/167) of cStage IIIB-IV LAD, respectively, showing a higher antibody response rate in more advanced stages. In the antibody-positive patients, CD4 and CD8 T cell responses were frequently elicited, and phenotypic and functional analyses of T cells indicated immune activation. Furthermore, the OS of antibody-positive patients significantly prolonged as compared with that of antibody-negative patients with either XAGE1 antigen-positive EGFRwt (31.5 vs 15.6 months, P = 0.05) or EGFRmt (34.7 vs 11.1 months, P = 0.001) LAD. Multivariate analysis showed that the XAGE1 antigen expression was a worse predictor in EGFRmt LAD (HR: 5.23). On the other hand, the presence of the XAGE1 antibody was a strong predictor for prolonged OS in XAGE1 antigen positive LAD (HR: 0.18) and in either EGFRwt or EGFRmt LAD. Conclusions: The XAGE1 antigen induced strong immune responses in LAD patients with more advanced stages, and the production of XAGE1 antibody in these patients showed good prognosis. Our results indicate that the XAGE1 immunity is probably a good prognostic biomarker in LAD and a promising target for immunotherapy of LAD.