Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma

Takahiro Tsujikawa; Kazuchika Ohno; Kei-Ichi Morita; Sumiyo Saburi; Junichi Mitsuda; Kanako Yoshimura; Alisa Kimura; Hiroki Morimoto; Hiroshi Ogi; Saya Shibata; Takumi Akashi; Morito Kurata; Issei Imoto; Yasushi Shimizu; Satoshi Kano; Akihito Watanabe; Tomoko Yamazaki; Yukinori Asada; Ryuichi Hayashi; Yuki Saito; Hiroyuki Ozawa; Kiyoaki Tsukahara; Nobuhiko Oridate; Daisuke Sano; Arata Horii; Yushi Ueki; Takashi Maruo; Nobuaki Mukoyama; Nobuhiro Hanai; Takahito Fukusumi; Hiroshi Iwai; Takuo Fujisawa; Takashi Fujii; Ken-Ichi Nibu; Shigemichi Iwae; Tsutomu Ueda; Nobuyuki Chikuie; Ryuji Yasumatsu; Mioko Matsuo; Hirohito Umeno; Takeharu Ono; Muneyuki Masuda; Satoshi Toh; Kyoko Itoh; Shigeru Hirano; Takahiro Asakage

doi:10.3389/fimmu.2024.1390873

Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma

Front Immunol. 2024 Jul 29:15:1390873. doi: 10.3389/fimmu.2024.1390873. eCollection 2024.

Authors

Takahiro Tsujikawa^#^{1

2}, Kazuchika Ohno^#³, Kei-Ichi Morita^#⁴, Sumiyo Saburi¹, Junichi Mitsuda¹, Kanako Yoshimura¹, Alisa Kimura¹, Hiroki Morimoto¹, Hiroshi Ogi^{5

6}, Saya Shibata⁶, Takumi Akashi⁷, Morito Kurata⁸, Issei Imoto⁹, Yasushi Shimizu¹⁰, Satoshi Kano¹¹, Akihito Watanabe¹², Tomoko Yamazaki¹³, Yukinori Asada¹⁴, Ryuichi Hayashi¹⁵, Yuki Saito¹⁶, Hiroyuki Ozawa¹⁷, Kiyoaki Tsukahara¹⁸, Nobuhiko Oridate¹⁹, Daisuke Sano¹⁹, Arata Horii²⁰, Yushi Ueki²⁰, Takashi Maruo²¹, Nobuaki Mukoyama²¹, Nobuhiro Hanai²², Takahito Fukusumi²³, Hiroshi Iwai²⁴, Takuo Fujisawa²⁴, Takashi Fujii²⁵, Ken-Ichi Nibu²⁶, Shigemichi Iwae²⁷, Tsutomu Ueda²⁸, Nobuyuki Chikuie²⁸, Ryuji Yasumatsu²⁹, Mioko Matsuo³⁰, Hirohito Umeno³¹, Takeharu Ono³¹, Muneyuki Masuda³², Satoshi Toh³², Kyoko Itoh⁵, Shigeru Hirano¹, Takahiro Asakage³

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
² Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, United States.
³ Department of Head and Neck Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Department of Maxillofacial Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
⁵ Department of Pathology and Applied Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
⁶ SCREEN Holdings, Kyoto, Japan.
⁷ Department of Diagnostic Pathology, Tokyo Medical and Dental University, Tokyo, Japan.
⁸ Department of Comprehensive Pathology, Tokyo Medical and Dental University, Tokyo, Japan.
⁹ Aichi Cancer Center Research Institute, Nagoya, Japan.
¹⁰ Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹¹ Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹² Department of Otolaryngology- Head and Neck Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan.
¹³ Department Head and Neck Oncology Division, Saitama Medical University International Medical Center, Hidaka, Japan.
¹⁴ Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Japan.
¹⁵ Department of Head and Neck Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
¹⁶ Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁷ Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan.
¹⁸ Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan.
¹⁹ Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.
²⁰ Department of Otolaryngology Head and Neck Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
²¹ Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²² Department of Head and Neck Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
²³ Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
²⁴ Department of Otolaryngology, Head and Neck Surgery, Kansai Medical University Hospital, Osaka, Japan.
²⁵ Department of Head and Neck Surgery, Osaka International Cancer Institute, Osaka, Japan.
²⁶ Department of Otolaryngology-Head and Neck Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.
²⁷ Department of Head and Neck Surgery, Hyogo Cancer Center, Akashi, Japan.
²⁸ Department of Otolaryngology and Head and Neck Surgery, Hiroshima University Hospital, Hiroshima, Japan.
²⁹ Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine, Kindai University, Osaka, Japan.
³⁰ Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³¹ Department of Otolaryngology-Head and Neck Surgery, Kurume University School of Medicine, Kurume, Japan.
³² Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

^# Contributed equally.

Abstract

Background: 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- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC.

Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing.

Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (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.

Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Keywords: biomarker; head and neck squamous cell carcinoma; immune profile; mutation; nivolumab.

Copyright © 2024 Tsujikawa, Ohno, Morita, Saburi, Mitsuda, Yoshimura, Kimura, Morimoto, Ogi, Shibata, Akashi, Kurata, Imoto, Shimizu, Kano, Watanabe, Yamazaki, Asada, 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.

Publication types

Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Immunological / adverse effects
Antineoplastic Agents, Immunological / therapeutic use
B7-H1 Antigen / genetics
Biomarkers, Tumor / genetics
Female
Genomics / methods
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / genetics
Head and Neck Neoplasms* / immunology
Humans
Immune Checkpoint Inhibitors / adverse effects
Immune Checkpoint Inhibitors / therapeutic use
Male
Middle Aged
Mutation
Nivolumab* / adverse effects
Nivolumab* / therapeutic use
Retrospective Studies
Squamous Cell Carcinoma of Head and Neck* / drug therapy
Squamous Cell Carcinoma of Head and Neck* / genetics
Squamous Cell Carcinoma of Head and Neck* / immunology
Treatment Outcome
Tumor Microenvironment* / immunology

Substances

Nivolumab
Biomarkers, Tumor
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
B7-H1 Antigen
CD274 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by grants from Ono pharmaceutical Co., Ltd. and Bristol Myers Squibb; the Japanese Ministry of Education, Culture, Sports, Science, and Technology (22K09688 and 23K15891); Japan Agency for Medical Research and Development (JP23zf0227002); the Public Promoting Association Asano Foundation for Studies on Medicine; and the Research Promotion Award from the Oto-Rhino-Laryngological Society of Japan, Inc. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.