Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma
Background There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoi...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000375.full |
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| author | Yukari Kobayashi Kazuhiro Kakimi Hirokazu Matsushita Kosei Hasegawa Katsutoshi Oda Shogo Yamamoto Kayo Asada Takahiro Karasaki Akira Yabuno Akira Nishijima Takahide Nejo Sho Sato Yuji Ikeda Manami Miyai Yusuke Takahashi Rui Yamaguchi Keiichi Fujiwara Hiroyuki Aburatani |
| author_facet | Yukari Kobayashi Kazuhiro Kakimi Hirokazu Matsushita Kosei Hasegawa Katsutoshi Oda Shogo Yamamoto Kayo Asada Takahiro Karasaki Akira Yabuno Akira Nishijima Takahide Nejo Sho Sato Yuji Ikeda Manami Miyai Yusuke Takahashi Rui Yamaguchi Keiichi Fujiwara Hiroyuki Aburatani |
| author_sort | Yukari Kobayashi |
| collection | DOAJ |
| description | Background There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors.Methods A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine BRCA1 and RAD51C promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed.Results As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAghiHLAhi) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAghiHLAhi) in HR-deficient HGSC.Conclusions Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition. |
| format | Article |
| id | doaj-art-83da46cfa4344dbd93bfcb670236fb67 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-83da46cfa4344dbd93bfcb670236fb672025-08-20T02:13:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000375Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinomaYukari Kobayashi0Kazuhiro Kakimi1Hirokazu Matsushita2Kosei Hasegawa3Katsutoshi Oda4Shogo Yamamoto5Kayo Asada6Takahiro Karasaki7Akira Yabuno8Akira Nishijima9Takahide Nejo10Sho Sato11Yuji Ikeda12Manami Miyai13Yusuke Takahashi14Rui Yamaguchi15Keiichi Fujiwara16Hiroyuki Aburatani171 Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan1The University of Tokyo Hospital, Tokyo, Bunkyo-ku, Japan4Aichi Cancer Center Research Institute, Nagoya, JapanSaitama Medical University International Medical Center, Gynecologic Oncology, Hidaka, Japan6 Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan7 Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan6 Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan1 Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, JapanSaitama Medical University International Medical Center, Saitama, Japan6 Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan1 Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japanundergraduate student)5 Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan3 Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, Aichi, JapanDivision of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, JapanDivision of Cancer Informatics, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Obstetrics and Gynecology, International University of Health and Welfare Narita Hospital, Narita, Chiba, JapanThe University of Tokyo, Bunkyo-ku, JapanBackground There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors.Methods A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine BRCA1 and RAD51C promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed.Results As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAghiHLAhi) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAghiHLAhi) in HR-deficient HGSC.Conclusions Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.https://jitc.bmj.com/content/8/1/e000375.full |
| spellingShingle | Yukari Kobayashi Kazuhiro Kakimi Hirokazu Matsushita Kosei Hasegawa Katsutoshi Oda Shogo Yamamoto Kayo Asada Takahiro Karasaki Akira Yabuno Akira Nishijima Takahide Nejo Sho Sato Yuji Ikeda Manami Miyai Yusuke Takahashi Rui Yamaguchi Keiichi Fujiwara Hiroyuki Aburatani Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma Journal for ImmunoTherapy of Cancer |
| title | Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma |
| title_full | Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma |
| title_fullStr | Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma |
| title_full_unstemmed | Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma |
| title_short | Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma |
| title_sort | neoantigen load and hla class i expression identify a subgroup of tumors with a t cell inflamed phenotype and favorable prognosis in homologous recombination proficient high grade serous ovarian carcinoma |
| url | https://jitc.bmj.com/content/8/1/e000375.full |
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