Tumor Microenvironments in Malignant Ovarian Germ Cell Tumors: MHC Class I Loss and T‐Cell Exhaustion in Dysgerminoma

ABSTRACT

Malignant ovarian germ cell tumors are rare neoplasms primarily affecting young women. Although generally responsive to chemotherapy, long‐term adverse effects remain a concern. Improved understanding of the tumor microenvironment may reveal alternative therapeutic strategies; however, comprehensive analyses in malignant ovarian germ cell tumors remain limited. We analyzed 56 malignant ovarian germ cell tumor samples: 23 dysgerminomas, 14 yolk sac tumors, and 19 immature teratomas. Immune cell infiltration and immune checkpoint molecule expression were evaluated via immunohistochemistry, while immune‐related gene expression was assessed using transcriptomic profiling. In dysgerminoma, T‐cell exhaustion was characterized through multiplex immunofluorescence. Major histocompatibility complex class I expression was assessed across all subtypes. Dysgerminomas showed abundant CD4 ⁺ and CD8 ⁺ T‐cell, B‐cell, and M1 macrophage infiltration, with the presence of tertiary lymphoid structures, indicating an immunologically active “hot tumor” phenotype. Immune checkpoint molecules were upregulated, and transcriptomic analysis revealed enrichment of immunostimulatory and immunosuppressive pathways. Conversely, yolk sac tumors were dominated by M2 macrophages, while immature teratomas exhibited minimal immune cell infiltration, a “cold tumor” feature. In dysgerminomas with high programmed cell death protein 1 levels, most CD8 ⁺ T cells exhibited a nonexhausted phenotype. All tumor subtypes showed loss of major histocompatibility complex class I expression. These findings indicate that malignant ovarian germ cell tumor subtypes harbor distinct tumor microenvironments, with dysgerminoma characterized by abundant but potentially ineffective T‐cell responses owing to absent major histocompatibility complex class I–mediated antigen presentation. Therapeutic strategies restoring major histocompatibility complex class I expression may enhance T cell–based immunotherapy efficacy in dysgerminomas.