Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study)
BackgroundNivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study...
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2025-01-01
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| author | Kuniaki Sato Satoshi Toh Taku Murakami Takafumi Nakano Takahiro Hongo Mioko Matsuo Kazuki Hashimoto Masashi Sugasawa Keisuke Yamazaki Yushi Ueki Torahiko Nakashima Hideoki Uryu Takeharu Ono Hirohito Umeno Tsutomu Ueda Satoshi Kano Kiyoaki Tsukahara Akihito Watanabe Ichiro Ota Nobuya Monden Shigemichi Iwae Takashi Maruo Yukinori Asada Nobuhiro Hanai Daisuke Sano Hiroyuki Ozawa Takahiro Asakage Takahito Fukusumi Muneyuki Masuda |
| author_facet | Kuniaki Sato Satoshi Toh Taku Murakami Takafumi Nakano Takahiro Hongo Mioko Matsuo Kazuki Hashimoto Masashi Sugasawa Keisuke Yamazaki Yushi Ueki Torahiko Nakashima Hideoki Uryu Takeharu Ono Hirohito Umeno Tsutomu Ueda Satoshi Kano Kiyoaki Tsukahara Akihito Watanabe Ichiro Ota Nobuya Monden Shigemichi Iwae Takashi Maruo Yukinori Asada Nobuhiro Hanai Daisuke Sano Hiroyuki Ozawa Takahiro Asakage Takahito Fukusumi Muneyuki Masuda |
| author_sort | Kuniaki Sato |
| collection | DOAJ |
| description | BackgroundNivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors.MethodsPre-treatment plasmas (N = 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples (N = 20) were assayed to elucidate biological implications of the PEX mRNA signature.ResultsAssays for pre-treatment blood samples (N = 104) demonstrated that a combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%; P = 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055; P = 0.0002348). Parallel biological assays demonstrated that in the paired treatment-naïve HNSCC tumor and plasma samples (N = 20), PEX HLA-E mRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein (P = 0.0191) and the dense population of tumor-infiltrating NK cells (P = 0.024) in the corresponding tumor, suggesting that the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade.ConclusionThe PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs. |
| format | Article |
| id | doaj-art-30e867b5cf4f482bbe470e67e0008887 |
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| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Frontiers in Immunology |
| spelling | doaj-art-30e867b5cf4f482bbe470e67e00088872025-08-20T02:36:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14644191464419Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study)Kuniaki Sato0Satoshi Toh1Taku Murakami2Takafumi Nakano3Takahiro Hongo4Mioko Matsuo5Kazuki Hashimoto6Masashi Sugasawa7Keisuke Yamazaki8Yushi Ueki9Torahiko Nakashima10Hideoki Uryu11Takeharu Ono12Hirohito Umeno13Tsutomu Ueda14Satoshi Kano15Kiyoaki Tsukahara16Akihito Watanabe17Ichiro Ota18Nobuya Monden19Shigemichi Iwae20Takashi Maruo21Yukinori Asada22Nobuhiro Hanai23Daisuke Sano24Hiroyuki Ozawa25Takahiro Asakage26Takahito Fukusumi27Muneyuki Masuda28Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, JapanDepartment of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, JapanShowa Denko Materials America, R&D Center, Irvine, CA, United StatesDepartment of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, JapanDepartment of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, JapanDepartment of Otolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Fukuoka, JapanDepartment of Otolaryngology, Head and Neck Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Fukuoka, JapanDepartment of Head & Neck Surgery, International Medical Center, Saitama Medical University, Hidaka, Saitama, JapanDepartment of Otolaryngology, Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, JapanDepartment of Otolaryngology, Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, JapanDepartment of Otorhinolaryngology, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka, JapanDepartment of Otorhinolaryngology, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka, JapanDepartment of Otolaryngology, Head and Neck Surgery, Kurume University School of Medicine, Kurume, Fukuoka, JapanDepartment of Otolaryngology, Head and Neck Surgery, Kurume University School of Medicine, Kurume, Fukuoka, JapanDepartment of Otorhinolaryngology, Head and Neck Surgery Graduate School of Biomedical and Health Sciences Hiroshima University, Hiroshima, Hiroshima, JapanDepartment of Otolaryngology, Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan0Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan1Department of Otolaryngology, Head and Neck Surgery, Keiyukai Sapporo Hospital, Sapporo, Hokkaido, Japan2Department of Otolaryngology-Head and Neck Surgery, Nara Medical University, Kashiwara, Nara, Japan3Department of Head and Neck Surgery, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan4Department of Head and Neck Surgery, Hyogo Cancer Center, Akashi, Hyogo, Japan5Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan6Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Miyagi, Japan7Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan8Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan9Keio University School of Medicine, Otolaryngology, Head and Neck Surgery, Tokyo, Japan0Department of Head and Neck Surgery, Tokyo Medical and Dental University, Tokyo, Japan1Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, JapanDepartment of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, JapanBackgroundNivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors.MethodsPre-treatment plasmas (N = 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples (N = 20) were assayed to elucidate biological implications of the PEX mRNA signature.ResultsAssays for pre-treatment blood samples (N = 104) demonstrated that a combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%; P = 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055; P = 0.0002348). Parallel biological assays demonstrated that in the paired treatment-naïve HNSCC tumor and plasma samples (N = 20), PEX HLA-E mRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein (P = 0.0191) and the dense population of tumor-infiltrating NK cells (P = 0.024) in the corresponding tumor, suggesting that the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade.ConclusionThe PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1464419/fullnivolumabhead and neck cancerbiomarkerexosomeHLA-E |
| spellingShingle | Kuniaki Sato Satoshi Toh Taku Murakami Takafumi Nakano Takahiro Hongo Mioko Matsuo Kazuki Hashimoto Masashi Sugasawa Keisuke Yamazaki Yushi Ueki Torahiko Nakashima Hideoki Uryu Takeharu Ono Hirohito Umeno Tsutomu Ueda Satoshi Kano Kiyoaki Tsukahara Akihito Watanabe Ichiro Ota Nobuya Monden Shigemichi Iwae Takashi Maruo Yukinori Asada Nobuhiro Hanai Daisuke Sano Hiroyuki Ozawa Takahiro Asakage Takahito Fukusumi Muneyuki Masuda Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study) Frontiers in Immunology nivolumab head and neck cancer biomarker exosome HLA-E |
| title | Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study) |
| title_full | Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study) |
| title_fullStr | Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study) |
| title_full_unstemmed | Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study) |
| title_short | Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study) |
| title_sort | nationwide multi centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mrnas from head and neck cancer patients bionext study |
| topic | nivolumab head and neck cancer biomarker exosome HLA-E |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1464419/full |
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