PMID- 32461346
OWN - NLM
STAT- MEDLINE
DCOM- 20210317
LR  - 20210317
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 8
IP  - 1
DP  - 2020 May
TI  - 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.
LID - 10.1136/jitc-2019-000375 [doi]
LID - e000375
AB  - 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 (neoAg(hi)HLA(hi)) 
      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-gamma 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 (neoAg(hi)HLA(hi)) 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.
CI  - (c) Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Matsushita, Hirokazu
AU  - Matsushita H
AUID- ORCID: 0000-0001-9069-7160
AD  - Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, 
      Tokyo, Japan h.matsushita@aichi-cc.jp koseih@saitama-med.ac.jp.
AD  - Cancer Immunology Data Multi-level Integration Unit, Medical Science Innovation 
      Hub Program, RIKEN, Chuo-ku, Tokyo, Japan.
AD  - Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, 
      Nagoya, Aichi, Japan.
AD  - Division of Cancer Immunogenomics, Nagoya University Graduate School of Medicine, 
      Nagoya, Aichi, Japan.
FAU - Hasegawa, Kosei
AU  - Hasegawa K
AD  - Department of Gynecologic Oncology, Saitama Medical University International 
      Medical Center, Hidaka, Saitama, Japan h.matsushita@aichi-cc.jp 
      koseih@saitama-med.ac.jp.
FAU - Oda, Katsutoshi
AU  - Oda K
AD  - Department of Obstetrics and Gynecology, The University of Tokyo Hospital, 
      Bunkyo-ku, Tokyo, Japan.
FAU - Yamamoto, Shogo
AU  - Yamamoto S
AD  - Genome Science Division, Research Center for Advanced Science and Technology, The 
      University of Tokyo, Meguro-ku, Tokyo, Japan.
FAU - Asada, Kayo
AU  - Asada K
AD  - Department of Obstetrics and Gynecology, The University of Tokyo Hospital, 
      Bunkyo-ku, Tokyo, Japan.
AD  - Genome Science Division, Research Center for Advanced Science and Technology, The 
      University of Tokyo, Meguro-ku, Tokyo, Japan.
FAU - Karasaki, Takahiro
AU  - Karasaki T
AD  - Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, 
      Tokyo, Japan.
AD  - Cancer Immunology Data Multi-level Integration Unit, Medical Science Innovation 
      Hub Program, RIKEN, Chuo-ku, Tokyo, Japan.
FAU - Yabuno, Akira
AU  - Yabuno A
AUID- ORCID: 0000-0002-1221-0609
AD  - Department of Gynecologic Oncology, Saitama Medical University International 
      Medical Center, Hidaka, Saitama, Japan.
FAU - Nishijima, Akira
AU  - Nishijima A
AD  - Department of Obstetrics and Gynecology, The University of Tokyo Hospital, 
      Bunkyo-ku, Tokyo, Japan.
AD  - Genome Science Division, Research Center for Advanced Science and Technology, The 
      University of Tokyo, Meguro-ku, Tokyo, Japan.
FAU - Nejo, Takahide
AU  - Nejo T
AD  - Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, 
      Tokyo, Japan.
FAU - Kobayashi, Yukari
AU  - Kobayashi Y
AD  - Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, 
      Tokyo, Japan.
FAU - Sato, Sho
AU  - Sato S
AD  - Department of Gynecologic Oncology, Saitama Medical University International 
      Medical Center, Hidaka, Saitama, Japan.
FAU - Ikeda, Yuji
AU  - Ikeda Y
AD  - Department of Gynecologic Oncology, Saitama Medical University International 
      Medical Center, Hidaka, Saitama, Japan.
AD  - Department of Obstetrics and Gynecology, The University of Tokyo Hospital, 
      Bunkyo-ku, Tokyo, Japan.
FAU - Miyai, Manami
AU  - Miyai M
AD  - Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, 
      Nagoya, Aichi, Japan.
FAU - Takahashi, Yusuke
AU  - Takahashi Y
AD  - Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, 
      Nagoya, Aichi, Japan.
FAU - Yamaguchi, Rui
AU  - Yamaguchi R
AD  - Division of Cancer Systems Biology, Aichi Cancer Center Research Institute, 
      Nagoya, Aichi, Japan.
AD  - Division of Cancer Informatics, Nagoya University Graduate School of Medicine, 
      Nagoya, Aichi, Japan.
FAU - Fujiwara, Keiichi
AU  - Fujiwara K
AD  - Department of Gynecologic Oncology, Saitama Medical University International 
      Medical Center, Hidaka, Saitama, Japan.
FAU - Aburatani, Hiroyuki
AU  - Aburatani H
AD  - Genome Science Division, Research Center for Advanced Science and Technology, The 
      University of Tokyo, Meguro-ku, Tokyo, Japan.
FAU - Kakimi, Kazuhiro
AU  - Kakimi K
AD  - Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, 
      Tokyo, Japan.
AD  - Cancer Immunology Data Multi-level Integration Unit, Medical Science Innovation 
      Hub Program, RIKEN, Chuo-ku, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Antigens, Neoplasm/*immunology
MH  - Cystadenocarcinoma, Serous/drug therapy/genetics/*immunology
MH  - Female
MH  - Histocompatibility Antigens Class I/genetics/*immunology/metabolism
MH  - *Homologous Recombination
MH  - Humans
MH  - Lymphocytes, Tumor-Infiltrating/*immunology
MH  - Middle Aged
MH  - Mutation
MH  - Ovarian Neoplasms/drug therapy/genetics/*immunology
MH  - Phenotype
MH  - Prognosis
MH  - Survival Rate
MH  - T-Lymphocytes/*immunology
PMC - PMC7254153
OTO - NOTNLM
OT  - immunology
OT  - tumor microenvironment
OT  - tumours
COIS- Competing interests: None declared.
EDAT- 2020/05/29 06:00
MHDA- 2021/03/18 06:00
PMCR- 2020/05/26
CRDT- 2020/05/29 06:00
PHST- 2020/04/07 00:00 [accepted]
PHST- 2020/05/29 06:00 [entrez]
PHST- 2020/05/29 06:00 [pubmed]
PHST- 2021/03/18 06:00 [medline]
PHST- 2020/05/26 00:00 [pmc-release]
AID - jitc-2019-000375 [pii]
AID - 10.1136/jitc-2019-000375 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2020 May;8(1):e000375. doi: 10.1136/jitc-2019-000375.