The human testis-specific protein Y-linked (TSPY) is a male-specific cancer-testis antigen capable of eliciting significant immune responses and elimination of positive tumor cells in hepatocellular carcinoma

TL;DR

The TSPY protein, found in testes and liver cancer, triggers strong immune responses early on but may later help cancer grow, making it a potential target for male-specific liver cancer treatments.

Contribution

TSPY is identified as a male-specific cancer-testis antigen that elicits immune responses and is a candidate for immunotherapies in hepatocellular carcinoma.

Findings

TSPY expression in a mouse model of HCC initially suppresses tumor growth but later promotes oncogenic progression.

TSPY elicits significant immune and inflammatory responses, leading to the elimination of positive tumor cells at early stages.

TSPY peptides form complexes with MHC-I molecules, triggering cytotoxic T cell responses and tumor cell killing.

Abstract

The testis-specific protein Y-linked (TSPY) is a male-specific cancer-testis antigen specifically expressed in germ cells of the testis under normal conditions and various cancers, particularly in hepatocellular carcinoma (HCC), under oncogenic conditions. It binds to cyclin B and exacerbates the cyclin B-CDK1 phosphorylation of factors important for mitotic/meiotic divisions. To determine if such TSPY proliferative actions could contribute to various male-biases in liver cancer, TSPY transgene was expressed in an oncogene-induced preclinical mouse model of HCC, using the hydrodynamic tail vein injection strategy. The results showed that TSPY expression suppressed tumor cell growth at early stage but could evolve to resume oncogenic progression at late stage in this mouse model. Transcriptome and bioinformatic analyses demonstrated that significant immune and inflammatory responses were activated in early stage of the cancer, resulting in elimination of positive tumor cells. Significant TSPY antibodies were present in the sera of positive mice, similar to the presence of autoantibodies in the sera of patients positive for TSPY in their tumors. Flow cytometry and cellular protein fractionation analyses of positive tumor cells showed that TSPY protein could be mislocalized on the cell surface and likely be responsible for the humoral immunity. Additional studies demonstrated that TSPY peptides were produced and could form complexes with MHC-I molecules and be presented on the cell surface, thereby eliciting robust cytotoxic T cell responses and killing of positive tumor cells. Importantly these immune responses diminished and TSPY could exacerbate oncogenic growth at late stage. These findings suggest that as a male-specific cancer-testis antigen, TSPY is extremely immunogenic capable of eliciting robust immune and inflammatory responses at the early stage and is a significant candidate for development of immunotherapeutics, such as therapeutic cancer vaccine and antibody-drug conjugates, in treatments of hepatocellular carcinoma in men.

The online version contains supplementary material available at 10.1186/s13578-025-01432-8.

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