AUTHOR=Tsujikawa Takahiro , Ohno Kazuchika , Morita Kei-ichi , Saburi Sumiyo , Mitsuda Junichi , Yoshimura Kanako , Kimura Alisa , Morimoto Hiroki , Ogi Hiroshi , Shibata Saya , Akashi Takumi , Kurata Morito , Imoto Issei , Shimizu Yasushi , Kano Satoshi , Watanabe Akihito , Yamazaki Tomoko , Asada Yukinori , Hayashi Ryuichi , Saito Yuki , Ozawa Hiroyuki , Tsukahara Kiyoaki , Oridate Nobuhiko , Sano Daisuke , Horii Arata , Ueki Yushi , Maruo Takashi , Mukoyama Nobuaki , Hanai Nobuhiro , Fukusumi Takahito , Iwai Hiroshi , Fujisawa Takuo , Fujii Takashi , Nibu Ken-ichi , Iwae Shigemichi , Ueda Tsutomu , Chikuie Nobuyuki , Yasumatsu Ryuji , Matsuo Mioko , Umeno Hirohito , Ono Takeharu , Masuda Muneyuki , Toh Satoshi , Itoh Kyoko , Hirano Shigeru , Asakage Takahiro TITLE=Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1390873 DOI=10.3389/fimmu.2024.1390873 ISSN=1664-3224 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.