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)

被引：0

作者：

Sato, Kuniaki ^{[1
]}

Toh, Satoshi ^{[1
]}

Murakami, Taku ^{[2
]}

Nakano, Takafumi ^{[1
]}

Hongo, Takahiro ^{[1
]}

Matsuo, Mioko ^{[3
]}

Hashimoto, Kazuki ^{[3
]}

Sugasawa, Masashi ^{[4
]}

Yamazaki, Keisuke ^{[5
]}

Ueki, Yushi ^{[5
]}

Nakashima, Torahiko ^{[6
]}

Uryu, Hideoki ^{[6
]}

Ono, Takeharu ^{[7
]}

Umeno, Hirohito ^{[7
]}

Ueda, Tsutomu ^{[8
]}

Kano, Satoshi ^{[9
,10
]}

Tsukahara, Kiyoaki ^{[11
]}

Watanabe, Akihito ^{[12
]}

Ota, Ichiro ^{[13
]}

Monden, Nobuya ^{[14
]}

Iwae, Shigemichi ^{[15
]}

Maruo, Takashi ^{[16
]}

Asada, Yukinori ^{[17
]}

Hanai, Nobuhiro ^{[18
]}

Sano, Daisuke ^{[19
]}

Ozawa, Hiroyuki ^{[20
]}

Asakage, Takahiro ^{[21
]}

Fukusumi, Takahito

Masuda, Muneyuki ^{[1
]}

机构：

[1] Natl Hosp Org Kyushu Canc Ctr, Dept Head & Neck Surg, Fukuoka, Fukuoka, Japan

[2] Showa Denko Mat Amer, R&D Ctr, Irvine, CA USA

[3] Kyushu Univ, Grad Sch Med Sci, Dept Otorhinolaryngol & Head & Neck Surg, Fukuoka, Fukuoka, Japan

[4] Saitama Med Univ, Int Med Ctr, Dept Head & Neck Surg, Hidaka, Saitama, Japan

[5] Niigata Univ, Grad Sch Med & Dent Sci, Dept Otolaryngol Head & Neck Surg, Niigata, Japan

[6] Natl Hosp Org Kyushu Med Ctr, Dept Otorhinolaryngol, Fukuoka, Fukuoka, Japan

[7] Kurume Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Kurume, Fukuoka, Japan

[8] Hiroshima Univ, Head & Neck Surg Grad Sch Biomed & Hlth Sci, Dept Otorhinolaryngol, Hiroshima, Japan

[9] Hokkaido Univ, Fac Med, Dept Otolaryngol Head & Neck Surg, Sapporo, Japan

[10] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan

[11] Tokyo Med Univ, Dept Otorhinolaryngol Head & Neck Surg, Tokyo, Japan

[12] Keiyukai Sapporo Hosp, Dept Otolaryngol Head & Neck Surg, Sapporo, Hokkaido, Japan

[13] Nara Med Univ, Dept Otolaryngol Head & Neck Surg, Kashiwara, Nara, Japan

[14] Natl Hosp Org Shikoku Canc Ctr, Dept Head & Neck Surg, Matsuyama, Ehime, Japan

[15] Hyogo Canc Ctr, Dept Head & Neck Surg, Akashi, Hyogo, Japan

[16] Nagoya Univ, Grad Sch Med, Dept Otorhinolaryngol, Nagoya, Aichi, Japan

[17] Miyagi Canc Ctr, Dept Head & Neck Surg, Natori, Miyagi, Japan

[18] Aichi Canc Ctr Hosp, Dept Head & Neck Surg, Nagoya, Aichi, Japan

[19] Yokohama City Univ, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Yokohama, Kanagawa, Japan

[20] Keio Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Tokyo, Japan

[21] Tokyo Med & Dent Univ, Dept Head & Neck Surg, Tokyo, Japan

来源：

FRONTIERS IN IMMUNOLOGY | 2025年 / 15卷

关键词：

nivolumab; head and neck cancer; biomarker; exosome; HLA-E; SQUAMOUS-CELL CARCINOMA; RECURRENT; PROFILE;

D O I：

10.3389/fimmu.2024.1464419

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Background: 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-na & iuml;ve tumor and plasma samples (N = 20) were assayed to elucidate biological implications of the PEX mRNA signature. Results: 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-na & iuml;ve 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. Conclusion: 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-qPCR-based pre-treatment measurement of PEX mRNAs.

引用

页数：13