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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1464419
This article is part of the Research Topic Community Series in Novel Biomarkers in Tumor Immunity and Immunotherapy: Volume II View all 11 articles

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)

Provisionally accepted
Kuniaki Sato Kuniaki Sato 1Satoshi Toh Satoshi Toh 1Taku Murakami Taku Murakami 2Takafumi Nakano Takafumi Nakano 1Takahiro Hongo Takahiro Hongo 1Mioko Matsuo Mioko Matsuo 3Kazuki Hashimoto Kazuki Hashimoto 3Masashi Sugasawa Masashi Sugasawa 4Keisuke Yamazaki Keisuke Yamazaki 5Yushi Ueki Yushi Ueki 5Torahiko Nakashima Torahiko Nakashima 6Hideoki Uryu Hideoki Uryu 6Takeharu Ono Takeharu Ono 7Hirohito Umeno Hirohito Umeno 7Tsutomu Ueda Tsutomu Ueda 8Satoshi Kano Satoshi Kano 9Kiyoaki Tsukahara Kiyoaki Tsukahara 10Akihito Watanabe Akihito Watanabe 11Ichiro Ota Ichiro Ota 12Nobuyuki Monden Nobuyuki Monden 13Shigemichi Iwae Shigemichi Iwae 14Takashi Maruo Takashi Maruo 15Yukinori Asada Yukinori Asada 16Nobuhiro Hanai Nobuhiro Hanai 17Daisuke Sano Daisuke Sano 18Hiroyuki Ozawa Hiroyuki Ozawa 19Takahiro Asakage Takahiro Asakage 20Takahito Fukusimi Takahito Fukusimi 21Muneyuki Masuda Muneyuki Masuda 1*
  • 1 National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
  • 2 Showa Denko America, R &D Center, Irvine, California, United States
  • 3 Kyushu University, Fukuoka, Fukuoka, Japan
  • 4 Saitama Medical Center, Saitama Medical University Hospital, Saitama Medical University, Saitama City, Japan
  • 5 Niigata University, Niigata, Niigata, Japan
  • 6 National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka, Japan
  • 7 Kurume University, Kurume, Fukuoka, Japan
  • 8 Hiroshima University Hospital, Hiroshima University, Hiroshima, Japan
  • 9 Hokkaido University, Sapporo, Hokkaidō, Japan
  • 10 Tokyo Medical University, Tokyo, Japan
  • 11 Keiyukai Sapporo Hospital, Sapporo, Hokkaidō, Japan
  • 12 Nara Prefectural University, Nara, Nara, Japan
  • 13 Shikoku Cancer Center, Matsuyama, Ehime, Japan
  • 14 Hyogo Prefectural Cancer Center, Akashi, Hyōgo, Japan
  • 15 Nagoya University, Nagoya, Aichi, Japan
  • 16 Miyagi Cancer Center, Natori, Miyagi, Japan
  • 17 Aichi Cancer Center, Nagoya, Aichi, Japan
  • 18 Yokohama City University Hospital, Yokohama, Kanagawa, Japan
  • 19 Keio University Hospital, Tokyo, Japan
  • 20 Tokyo Medical and Dental University, Tokyo, Japan
  • 21 Osaka University, Suita, Ōsaka, Japan

The final, formatted version of the article will be published soon.

    BACKGROUNF Nivolumab 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.METHODS Pre-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.Assays 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.The 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-qPCRbased pre-treatment measurement of PEX mRNAs.

    Keywords: Nivolumab, head and neck cancer, biomarker, exosome, HLA-E

    Received: 14 Jul 2024; Accepted: 13 Dec 2024.

    Copyright: © 2024 Sato, Toh, Murakami, Nakano, Hongo, Matsuo, Hashimoto, Sugasawa, Yamazaki, Ueki, Nakashima, Uryu, Ono, Umeno, Ueda, Kano, Tsukahara, Watanabe, Ota, Monden, Iwae, Maruo, Asada, Hanai, Sano, Ozawa, Asakage, Fukusimi and Masuda. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Muneyuki Masuda, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.