Abstract
The cancer/testis antigen XAGE1 (GAGED2a) is expressed in approximately 40% of advanced lung adenocarcinomas. We investigated the clinical relevance of the XAGE1 (GAGED2a) immune responses in patients with advanced lung adenocarcinoma. The XAGE1 (GAGED2a) antigen expression and EGFR mutation were determined with tumor tissues. The XAGE1 (GAGED2a) antibody and T-cell immune responses, as well as immune cell phenotypes, were analyzed with blood samples. Patients with EGFR wild-type (EGFRwt) tumors were treated with conventional platinum-based doublet chemotherapy and patients with EGFR-mutated (EGFRmt) tumors were treated with EGFR-TKI and conventional chemotherapy. The overall survival (OS) rates of the antibody-positive and -negative patients were investigated. The results showed that the OS of antibody-positive patients was prolonged significantly compared with that of antibody-negative patients with either XAGE1 (GAGED2a) antigen-positive EGFRwt (31.5 vs. 15.6 months, P = 0.05) or EGFRmt (34.7 vs. 11.1 months, P = 0.001) tumors. Multivariate analysis showed that the presence of the XAGE1 (GAGED2a) antibody was a strong predictor for prolonged OS in patients with XAGE1 (GAGED2a) antigen-positive tumors and in patients with either EGFRwt or EGFRmt tumors. On the other hand, XAGE1 (GAGED2a) antigen expression was a worse predictor in patients with EGFRmt tumors. Phenotypic and functional analyses of T cells indicated immune activation in the antibody-positive patients. The findings suggest that production of the XAGE1 (GAGED2a) antibody predicts good prognosis for patients with lung adenocarcinoma as an immune biomarker and the protective effect of this naturally occurring immune response supports the concept of immunotherapy.
Highlights
Cancer/testis (CT) antigen is a class of antigens that express predominantly in the testes in normal adult tissues and in various tumors [1,2,3]
The results showed that the overall survival (OS) of antibody-positive patients was prolonged significantly compared with that of antibody-negative patients with either XAGE1 (GAGED2a) antigen-positive EGFR wild-type (EGFRwt) (31.5 vs. 15.6 months, P 1⁄4 0.05) or EGFRmt (34.7 vs. 11.1 months, P 1⁄4 0.001) tumors
Multivariate analysis showed that the presence of the XAGE1 (GAGED2a) antibody was a strong predictor for prolonged OS in patients with XAGE1 (GAGED2a) antigen-positive tumors and in patients with either EGFRwt or EGFRmt tumors
Summary
Cancer/testis (CT) antigen is a class of antigens that express predominantly in the testes in normal adult tissues and in various tumors [1,2,3]. XAGE1 was originally identified by the search for PAGE/ GAGE-related genes using an expression sequence tag database [9] and was shown to exhibit CT antigen characteristics [10, 11]. The associated protein is designated as a G antigen family D member 2 (GAGED2), and GAGED2a and d isoforms have been identified [9, 12]. Four transcript variants XAGE-1a, b, c, and d have been extensively studied and shown to be expressed in various tumors [13,14,15,16]. The XAGE-1a and b transcripts code for 81 amino acid XAGE1 (GAGED2a) protein, whereas the XAGE-1d transcript codes for a 69 amino acid XAGE1 (GAGED2d) protein [17]
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