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Brachyury-targeted immunotherapy combined with gemcitabine against head and neck cancer

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Abstract

Brachyury is a transcription factor belonging to the T-box gene family and is involved in the posterior formation of the mesoderm and differentiation of chordates. As the overexpression of Brachyury is a poor prognostic factor in a variety of cancers, the establishment of Brachyury-targeted therapy would be beneficial for the treatment of aggressive tumors. Because transcription factors are difficult to treat with a therapeutic antibody, peptide vaccines are a feasible approach for targeting Brachyury. In this study, we identified Brachyury-derived epitopes that elicit antigen-specific and tumor-reactive CD4+ T cells that directly kill tumors. T cells recognizing Brachyury epitopes were present in patients with head and neck squamous cell carcinoma. Next, we focused on gemcitabine (GEM) as an immunoadjuvant to augment the efficacy of antitumor responses by T cells. Interestingly, GEM upregulated HLA class I and HLA-DR expression in tumor, followed by the upregulation of anti-tumor T cell responses. As tumoral PD-L1 expression was also augmented by GEM, PD-1/PD-L1 blockade and GEM synergistically enhanced the tumor-reactivity of Brachyury-reactive T cells. The synergy between the PD-1/PD-L1 blockade and GEM was also confirmed in a mouse model of head and neck squamous cell carcinoma. These results suggest that the combined treatment of Brachyury peptide with GEM and immune checkpoint blockade could be a promising immunotherapy against head and neck cancer.

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Data availability

All data relevant to the study are included in the article or uploaded as supplementary information.

Abbreviations

Abs:

Antibodies

ATP:

Adenosine triphosphate

APC:

Antigen-presenting cell

CDDP:

Cisplatin

CTL:

CD8+ cytotoxic T lymphocyte

DAMPs:

Damage-associated molecular patterns

DC:

Dendritic cell

E:T:

Effector:Target

EMT:

Epithelial-mesenchymal transition

GEM:

Gemcitabine

HMGB1:

High mobility group box 1

HNSCC:

Head and neck squamous cell carcinoma

HTL:

CD4+ helper T lymphocyte

ICI:

Immune checkpoint inhibitor

mAb:

Monoclonal antibody

MFI:

Mean fluorescence intensity

NLR:

Neutrophil–Lymphocyte ratio

PBMC:

Peripheral blood mononuclear cell

SD:

Standard deviation

SUV:

Standardized uptake value

TILs:

Tumor infiltrating lymphocytes

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Acknowledgements

The authors also thank Dr. Hajime Kamada (Hokuto Social Medical Corporation) for his excellent suggestions for the manuscript.

Funding

This work was supported by JSPS KAKENHI Grant Number 20K09724 and 21H03082.

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Author notes

  1. Hidekiyo Yamaki, Michihisa Kono and Risa Wakisaka have been contributed equally to the work.

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan

    Hidekiyo Yamaki, Michihisa Kono, Risa Wakisaka, Hiroki Komatsuda, Takumi Kumai, Ryusuke Hayashi, Ryosuke Sato, Kenzo Ohara, Kan Kishibe, Miki Takahara, Tatsuya Hayashi & Akihiro Katada

  2. Department of Innovative Head and Neck Cancer Research and Treatment, Asahikawa Medical University, Asahikawa, Japan

    Takumi Kumai & Miki Takahara

  3. Department of Pathology, Asahikawa Medical University, Asahikawa, Japan

    Toshihiro Nagato, Takayuki Ohkuri, Akemi Kosaka & Hiroya Kobayashi

Authors
  1. Hidekiyo Yamaki
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  2. Michihisa Kono
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  3. Risa Wakisaka
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  4. Hiroki Komatsuda
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  5. Takumi Kumai
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  6. Ryusuke Hayashi
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  7. Ryosuke Sato
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Contributions

Acquisition, analysis, and interpretation of data: HY, MK, TK, RH, RS, HKom, HK, RW, and KO. Statistical analysis of data: KK, MT, and AKa. Material support: TN, TO, AKo, and HKob. Development of methodology: TK and TH. Conception, design and supervision of the study: TK. Writing of the paper: HY and TK. Review of the paper: TK and Aka.

Corresponding author

Correspondence to Takumi Kumai.

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Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval

All experiments were approved by the institutional ethics committee on the Asahikawa Medical University (#16217). The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

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The patients have given their written informed consent to participate and publish their case. The experimental protocol was approved by the Institutional Animal Care and Use Committee of Asahikawa Medical University (#20001).

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Yamaki, H., Kono, M., Wakisaka, R. et al. Brachyury-targeted immunotherapy combined with gemcitabine against head and neck cancer. Cancer Immunol Immunother 72, 2799–2812 (2023). https://doi.org/10.1007/s00262-023-03460-0

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