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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1390873
This article is part of the Research Topic A Rational Precision Therapeutics Approach to Target Rare Cancers View all articles
Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma
Provisionally accepted
Takahiro Tsujikawa
1
Kazuchika Ohno
2*
Kei-ichi Morita
2*
Sumiyo Saburi
1
Junichi Mitsuda
1
Kanako Yoshimura
1
Alisa Kimura
1*
Hiroki Morimoto
1*
Hiroshi Ogi
3
Saya Shibata
3*
Takumi Akashi
2
MORITO KURATA
2
Issei Imoto
4
Yasushi Shimizu
5
Satoshi Kano
5
Akihito Watanabe
6*
Yukinori Asada
7*
Tomoko Yamazaki
8*
Ryuichi Hayashi
9
Yuki Saito
10
Hiroyuki Ozawa
11
Kiyoaki Tsukahara
12
Nobuhiko Oridate
13
Daisuke Sano
13
Arata Horii
14
Yushi Ueki
14
Takashi Maruo
15*
Nobuaki Mukoyama
15*
Nobuhiro Hanai
4
Takahito Fukusumi
16*
Hiroshi Iwai
17*
Takuo Fujisawa
18*
Takashi Fujii
19*
Ken-ichi Nibu
20
Shigemichi Iwae
21*
Tsutomu Ueda
22*
Nobuyuki Chikuie
22*
Ryuji Yasumatsu
23*
Mioko Matsuo
24*
Hirohito Umeno
25
Takeharu Ono
25
Muneyuki Masuda
26
Satoshi Toh
26*
Kyoko Itoh
1
Shigeru Hirano
1*
Takahiro Asakage
2*- 1 Kyoto Prefectural University of Medicine, Kyoto, Japan
- 2 Tokyo Medical and Dental University, Tokyo, Japan
- 3 Independent researcher, Kyoto, Japan
- 4 Aichi Cancer Center, Nagoya, Aichi, Japan
- 5 Hokkaido University, Sapporo, Hokkaidō, Japan
- 6 Keiyukai Sapporo Hospital, Sapporo, Hokkaidō, Japan
- 7 Miyagi Cancer Center, Natori, Miyagi, Japan
- 8 Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
- 9 National Cancer Center Hospital East, Kashiwa, Chiba, Japan
- 10 The University of Tokyo, Bunkyo, Tōkyō, Japan
- 11 School of Medicine, Keio University, Tokyo, Japan
- 12 Tokyo Medical University, Tokyo, Japan
- 13 Yokohama City University, Yokohama, Kanagawa, Japan
- 14 Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
- 15 Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan
- 16 Graduate School of Medicine, Osaka University, Suita, Ōsaka, Japan
- 17 Kansai Medical University, Hirakata, Osaka, Japan
- 18 Kansai Medical University Hospital, Hirakata, Osaka, Japan
- 19 Osaka International Cancer Institute, Osaka, Osaka, Japan
- 20 Kobe University, Kobe, Hyōgo, Japan
- 21 Hyogo Prefectural Cancer Center, Akashi, Hyōgo, Japan
- 22 Hiroshima University, Hiroshima, Hiroshima, Japan
- 23 Kindai University, Higashi-osaka, Ōsaka, Japan
- 24 Kyushu University, Fukuoka, Fukuoka, Japan
- 25 School of Medicine, Kurume University, Kurume, Fukuoka, Japan
- 26 National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, Japan
In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti-PD-1 antibody, nivolumab, in patients with R/M HNSCC. The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-L1 expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. These findings indicate that nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.
Keywords: Head and neck squamous cell carcinoma, Nivolumab, biomarker, Immune profile, Mutation
Received: 24 Feb 2024; Accepted: 05 Jul 2024.
Copyright: © 2024 Tsujikawa, Ohno, Morita, Saburi, Mitsuda, Yoshimura, Kimura, Morimoto, Ogi, Shibata, Akashi, KURATA, Imoto, Shimizu, Kano, Watanabe, Asada, Yamazaki, Hayashi, Saito, Ozawa, Tsukahara, Oridate, Sano, Horii, Ueki, Maruo, Mukoyama, Hanai, Fukusumi, Iwai, Fujisawa, Fujii, Nibu, Iwae, Ueda, Chikuie, Yasumatsu, Matsuo, Umeno, Ono, Masuda, Toh, Itoh, Hirano and Asakage. 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:
Kazuchika Ohno, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
Kei-ichi Morita, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
Alisa Kimura, Kyoto Prefectural University of Medicine, Kyoto, Japan
Hiroki Morimoto, Kyoto Prefectural University of Medicine, Kyoto, Japan
Saya Shibata, Independent researcher, Kyoto, Japan
Akihito Watanabe, Keiyukai Sapporo Hospital, Sapporo, Hokkaidō, Japan
Yukinori Asada, Miyagi Cancer Center, Natori, 981-1293, Miyagi, Japan
Tomoko Yamazaki, Saitama Medical University International Medical Center, Hidaka, 350-1298, Saitama, Japan
Takashi Maruo, Graduate School of Medicine, Nagoya University, Nagoya, 466-8550, Aichi, Japan
Nobuaki Mukoyama, Graduate School of Medicine, Nagoya University, Nagoya, 466-8550, Aichi, Japan
Takahito Fukusumi, Graduate School of Medicine, Osaka University, Suita, 565-0871, Ōsaka, Japan
Hiroshi Iwai, Kansai Medical University, Hirakata, 573-1010, Osaka, Japan
Takuo Fujisawa, Kansai Medical University Hospital, Hirakata, 573-1191, Osaka, Japan
Takashi Fujii, Osaka International Cancer Institute, Osaka, 540-0008, Osaka, Japan
Shigemichi Iwae, Hyogo Prefectural Cancer Center, Akashi, Hyōgo, Japan
Tsutomu Ueda, Hiroshima University, Hiroshima, 739-8511, Hiroshima, Japan
Nobuyuki Chikuie, Hiroshima University, Hiroshima, 739-8511, Hiroshima, Japan
Ryuji Yasumatsu, Kindai University, Higashi-osaka, 577-8502, Ōsaka, Japan
Mioko Matsuo, Kyushu University, Fukuoka, 812-8581, Fukuoka, Japan
Satoshi Toh, National Hospital Organization Kyushu Cancer Center, Fukuoka, 810-0065, Fukuoka, Japan
Shigeru Hirano, Kyoto Prefectural University of Medicine, Kyoto, Japan
Takahiro Asakage, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
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