H Takami1,2, S Fukushima1, K Aoki3, K Satomi1,4, K Narumi3, N Hama5, Y Matsushita1,6, K Fukuoka1,7, K Yamasaki1,8, T Nakamura1,9, A Mukasa2,10, N Saito2, T Suzuki11, T Yanagisawa7, H Nakamura10,12, K Sugiyama13, K Tamura14, T Maehara14, M Nakada15, M Nonaka16, A Asai16, K Yokogami17, H Takeshima17, T Iuchi18, Y Kanemura19,20, K Kobayashi21, M Nagane21, K Kurozumi22, K Yoshimoto23, M Matsuda24, A Matsumura24, Y Hirose25, T Tokuyama26, T Kumabe27, K Ueki28, Y Narita6, S Shibui6, Y Totoki5, T Shibata5, Y Nakazato29, R Nishikawa9, M Matsutani9, K Ichimura1. 1. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan. 2. Department of Neurosurgery, Faculty of Medicine, The University of Tokyo Hospital, Tokyo, Japan. 3. Division of Gene and Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan. 4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan. 5. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. 6. Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan. 7. Division of Pediatric Neuro-Oncology, Saitama Medical University International Medical Center, Saitama, Japan. 8. Department of Pediatrics, Osaka City General Hospital, Osaka, Japan. 9. Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Kanagawa, Japan. 10. Department of Neurosurgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. 11. Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan. 12. Department of Neurosurgery, Kurume University, Fukuoka, Japan. 13. Department of Neurosurgery, Faculty of Medicine, Hiroshima University, Hiroshima, Japan. 14. Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. 15. Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan. 16. Department of Neurosurgery, Kansai Medical University Hospital, Osaka, Japan. 17. Department of Neurosurgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. 18. Department of Neurosurgery, Chiba Cancer Center, Chiba, Japan. 19. Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan. 20. Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka, Japan. 21. Department of Neurosurgery, Faculty of Medicine, Kyorin University, Tokyo, Japan. 22. Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan. 23. Department of Neurosurgery, Kyusyu University Hospital, Fukuoka, Japan. 24. Department of Neurosurgery, University of Tsukuba Hospital, Ibaraki, Japan. 25. Department of Neurosurgery, Fujita Health University Hospital, Aichi, Japan. 26. Department of Neurosurgery, Hamamatsu University Hospital, Shizuoka, Japan. 27. Department of Neurosurgery, Kitasato University, Kanagawa, Japan. 28. Department of Neurosurgery, Dokkyo Medical Univeristy, Tochigi, Japan. 29. Department of Pathology, Hidaka Hospital, Gunma, Japan.
Abstract
AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.
AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS:Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.