RRC ID 78616
Author Yamaki H, Kono M, Wakisaka R, Komatsuda H, Kumai T, Hayashi R, Sato R, Nagato T, Ohkuri T, Kosaka A, Ohara K, Kishibe K, Takahara M, Hayashi T, Kobayashi H, Katada A.
Title Brachyury-targeted immunotherapy combined with gemcitabine against head and neck cancer.
Journal Cancer Immunol Immunother
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.
Volume 72(8)
Pages 2799-2812
Published 2023-8-1
DOI 10.1007/s00262-023-03460-0
PII 10.1007/s00262-023-03460-0
PMID 37173455
MeSH Animals B7-H1 Antigen / metabolism Cell Line, Tumor Epitopes Gemcitabine* Head and Neck Neoplasms* / therapy Immunotherapy / methods Mice Programmed Cell Death 1 Receptor Squamous Cell Carcinoma of Head and Neck / therapy
Human and Animal Cells HSC-2(RCB1945) HSC-3(RCB1975) HSC-4(RCB1902)