Kido Tatsuo, Lau Yun-Fai Chris
Laboratory of Cell and Developmental Genetics, Department of Medicine, San Francisco VA Health Care System, Institute for Human Genetics, University of California, 94121, San Francisco, US, CA.
Cell Biosci. 2025 Jun 25;15(1):88. doi: 10.1186/s13578-025-01432-8.
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.
Y 染色体连锁的睾丸特异性蛋白（TSPY）是一种男性特异性的癌-睾丸抗原，在正常情况下特异性表达于睾丸生殖细胞，在致癌条件下也表达于各种癌症，尤其是肝细胞癌（HCC）。它与细胞周期蛋白 B 结合，加剧对有丝分裂/减数分裂重要的因子的细胞周期蛋白 B-CDK1 磷酸化。为了确定这种 TSPY 的增殖作用是否会导致肝癌中各种男性偏向性，利用尾静脉液压注射策略，在致癌基因诱导的 HCC 临床前小鼠模型中表达 TSPY 转基因。结果显示，在该小鼠模型中，TSPY 表达在早期抑制肿瘤细胞生长，但在后期可能会演变为恢复致癌进程。转录组和生物信息学分析表明，在癌症早期激活了显著的免疫和炎症反应，导致阳性肿瘤细胞被清除。阳性小鼠血清中存在显著的 TSPY 抗体，类似于肿瘤中 TSPY 阳性患者血清中自身抗体的存在。对阳性肿瘤细胞的流式细胞术和细胞蛋白分级分析表明，TSPY 蛋白可能在细胞表面错误定位，可能是体液免疫的原因。进一步研究表明，TSPY 肽产生并能与 MHC-I 分子形成复合物并呈递在细胞表面，从而引发强烈的细胞毒性 T 细胞反应并杀死阳性肿瘤细胞。重要的是，这些免疫反应在后期减弱，TSPY 会加剧致癌生长。这些发现表明，作为一种男性特异性的癌-睾丸抗原，TSPY 具有极强的免疫原性，能够在早期引发强烈的免疫和炎症反应，是开发免疫疗法（如治疗性癌症疫苗和抗体-药物偶联物）用于治疗男性肝细胞癌的重要候选物。
