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Tumor Microenvironments in Malignant Ovarian Germ Cell Tumors: MHC Class I Loss and T-Cell Exhaustion in Dysgerminoma
Miya Nakashima1,2, Takeshi Iwasaki1, Yoshihiro Katayama2
1Departments of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Insights
Malignant ovarian germ cell tumors have distinct tumor microenvironments. Dysgerminomas are immunologically active but may resist therapy due to lost Major Histocompatibility Complex class I expression, impacting T-cell responses.
Area of Science:
- Oncology
- Immunology
- Gynecologic Pathology
Background:
- Malignant ovarian germ cell tumors (OGCTs) primarily affect young women and, while chemotherapy-responsive, pose long-term adverse effect concerns.
- Understanding the tumor microenvironment (TME) is crucial for developing alternative therapeutic strategies for rare OGCTs.
- Comprehensive TME analyses in OGCT subtypes remain limited.
Purpose of the Study:
- To characterize the distinct tumor microenvironments of major malignant ovarian germ cell tumor subtypes.
- To evaluate immune cell infiltration, immune checkpoint molecule expression, and immune-related gene expression across OGCT subtypes.
- To assess the potential impact of TME characteristics on therapeutic responses.
Main Methods:
- Analysis of 56 malignant ovarian germ cell tumor samples (23 dysgerminomas, 14 yolk sac tumors, 19 immature teratomas).
- Immunohistochemistry for immune cell infiltration and immune checkpoint molecule expression.
- Transcriptomic profiling for immune-related gene expression.
- Multiplex immunofluorescence for T-cell exhaustion assessment in dysgerminomas.
- Evaluation of Major Histocompatibility Complex class I expression across all subtypes.
Main Results:
- Dysgerminomas exhibited an immunologically "hot" TME with abundant T-cells, B-cells, M1 macrophages, and tertiary lymphoid structures, alongside upregulated immune checkpoints.
- Yolk sac tumors were characterized by M2 macrophage dominance, while immature teratomas showed minimal immune infiltration (a "cold" TME).
- All OGCT subtypes displayed a loss of Major Histocompatibility Complex class I expression, potentially impairing T-cell recognition and antigen presentation.
Conclusions:
- Malignant ovarian germ cell tumor subtypes possess unique tumor microenvironments.
- Dysgerminomas, despite being immunologically active, may have ineffective T-cell responses due to absent Major Histocompatibility Complex class I expression.
- Restoring Major Histocompatibility Complex class I expression could be a therapeutic strategy to improve T cell-based immunotherapy efficacy in dysgerminomas.
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