Cancer-testis antigens as prognostic biomarkers and immune modulators in adenocarcinomas

Abstract Background Adenocarcinomas often exhibit a poor response to immunotherapy due to their "cold tumor" nature and immunosuppressive microenvironment. Cancer-testis antigens (CTAs), which are selectively expressed in tumors but absent in most normal tissues, represent ideal targets for tumor-specific therapies. Despite promising individual CTAs like MAGE-A, MSLN, and PRAME, a systematic analysis of their role across various adenocarcinomas is lacking. Methods In this study, we explored the expression profiles, prognostic significance, and immunomodulatory roles of cancer-testis antigens (CTAs) across various types of adenocarcinomas. By integrating data from The Cancer Genome Atlas (TCGA) with a validation cohort of 198 patients, comprising cases of colon, rectal, and lung adenocarcinomas, we analyzed six CTAs (CT83, MAGEA1, MAGEA4, MAGEA10, MSLN, and PRAME) utilizing survival analysis and immunohistochemistry techniques. Results Our findings revealed that CTAs exhibit tumor type-specific expression profiles. Notably, MSLN was highly expressed in colon adenocarcinoma (COAD, 73%), rectal adenocarcinoma (READ, 69%), and lung adenocarcinoma (LUAD, 72%), whereas PRAME was exclusively expressed in LUAD (24%). Elevated levels of CT83 ( p = 0.026) and MAGEA10 ( p = 0.036) in COAD, MAGEA1 ( p = 0.028) in READ, MAGEA1 ( p = 0.008) and MAGEA4 ( p = 0.009) in LUAD, were significantly associated with shorter progression-free survival (PFS). Additionally, exploratory CTA-count analysis showed that the prognostically relevant cutoff differed across tumor types, with more than one CTA-positive marker associated with poorer progression-free survival in COAD and more than two CTA-positive markers associated with poorer progression-free survival in READ and LUAD (COAD: p = 0.008; READ: p = 0.012; LUAD: p = 0.045). In LUAD, CT83 and MAGEA1 expression were significantly associated with lower infiltration of B cells, CD4 + T cells, and dendritic cells (all p < 0.01), and with higher infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs, p < 0.001) and FOXP3 + regulatory T cells (Tregs, p < 0.05). These effects were corroborated in the validation cohort of COAD (MAGEA4-Tregs, p < 0.05) and LUAD (CT83-Tregs, p < 0.05). Conclusions We found that CTA expression was highly tumor-type-specific in adenocarcinomas. These findings provide preliminary evidence for the potential relevance of CTA-based stratification in adenocarcinomas and may inform future mechanistic studies and prospective evaluation of precision immunotherapeutic strategies.