PD-L1-specific helper T-cells exhibit effective antitumor responses

New strategy of cancer immunotherapy targeting PD-L1 in head and neck squamous cell carcinoma

Yui Hirata-Nozaki, Takayuki Ohkuri, Kenzo Ohara, Takumi Kumai, Marino Nagata, Shohei Harabuchi, Akemi Kosaka, Toshihiro Nagato, Kei Ishibashi, Kensuke Oikawa, Naoko Aoki, Mizuho Ohara, Yasuaki Harabuchi, Yuji Uno, Hidehiro Takei, Esteban Celis, Hiroya Kobayashi

Research output: Contribution to journalArticle

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) originates from squamous epithelium of the upper aerodigestive tract and is the most common malignancy in the head and neck region. Among HNSCCs, oropharynx squamous cell carcinoma (OSCC) has a unique profile and is associated with human papillomavirus infection. Recently, anti-programmed cell death-1 monoclonal antibody has yielded good clinical responses in recurrent and/or metastatic HNSCC patients. Therefore, programmed death-ligand 1 (PD-L1) may be a favorable target molecule for cancer immunotherapy. Although PD-L1-expressing malignant cells could be targeted by PD-L1-specific CD8+ cytotoxic T lymphocytes, it remains unclear whether CD4+ helper T lymphocytes (HTLs) recognize and kill tumor cells in a PD-L1-specific manner. Methods: The expression levels of PD-L1 and HLA-DR were evaluated using immunohistochemical analyses. MHC class II-binding peptides for PD-L1 were designed based on computer algorithm analyses and added into in vitro culture of HTLs with antigen-presenting cells to evaluate their stimulatory activity. Results: We found that seven of 24 cases of OSCC showed positive for both PD-L1 and HLA-DR and that PD-L1241-265 peptide efficiently activates HTLs, which showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-dependent manner. Also, an adoptive transfer of the PD-L1-specific HTLs significantly inhibited growth of PD-L1-expressing human tumor cell lines in an immunodeficient mouse model. Importantly, T cell responses specific for the PD-L1241-265 peptide were detected in the HNSCC patients. Conclusions: The cancer immunotherapy targeting PD-L1 as a helper T-cell antigen would be a rational strategy for HNSCC patients.

Original languageEnglish (US)
Article number207
JournalJournal of Translational Medicine
Volume17
Issue number1
DOIs
StatePublished - Jun 20 2019

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Th1 Cells
T-cells
Immunotherapy
Ligands
Helper-Inducer T-Lymphocytes
Neoplasms
Tumors
Oropharynx
Cells
HLA-DR Antigens
Peptides
Squamous Cell Carcinoma
Carcinoma, squamous cell of head and neck
Epithelial Cells
Papillomavirus Infections
Adoptive Transfer
Viral Tumor Antigens
Cytotoxic T-Lymphocytes
Antigen-Presenting Cells
Cell death

Keywords

  • Cancer immunotherapy
  • Head and neck squamous cell carcinoma
  • Helper T-cells
  • PD-L1
  • Tumor-associated antigen

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

PD-L1-specific helper T-cells exhibit effective antitumor responses : New strategy of cancer immunotherapy targeting PD-L1 in head and neck squamous cell carcinoma. / Hirata-Nozaki, Yui; Ohkuri, Takayuki; Ohara, Kenzo; Kumai, Takumi; Nagata, Marino; Harabuchi, Shohei; Kosaka, Akemi; Nagato, Toshihiro; Ishibashi, Kei; Oikawa, Kensuke; Aoki, Naoko; Ohara, Mizuho; Harabuchi, Yasuaki; Uno, Yuji; Takei, Hidehiro; Celis, Esteban; Kobayashi, Hiroya.

In: Journal of Translational Medicine, Vol. 17, No. 1, 207, 20.06.2019.

Research output: Contribution to journalArticle

Hirata-Nozaki, Y, Ohkuri, T, Ohara, K, Kumai, T, Nagata, M, Harabuchi, S, Kosaka, A, Nagato, T, Ishibashi, K, Oikawa, K, Aoki, N, Ohara, M, Harabuchi, Y, Uno, Y, Takei, H, Celis, E & Kobayashi, H 2019, 'PD-L1-specific helper T-cells exhibit effective antitumor responses: New strategy of cancer immunotherapy targeting PD-L1 in head and neck squamous cell carcinoma', Journal of Translational Medicine, vol. 17, no. 1, 207. https://doi.org/10.1186/s12967-019-1957-5
Hirata-Nozaki, Yui ; Ohkuri, Takayuki ; Ohara, Kenzo ; Kumai, Takumi ; Nagata, Marino ; Harabuchi, Shohei ; Kosaka, Akemi ; Nagato, Toshihiro ; Ishibashi, Kei ; Oikawa, Kensuke ; Aoki, Naoko ; Ohara, Mizuho ; Harabuchi, Yasuaki ; Uno, Yuji ; Takei, Hidehiro ; Celis, Esteban ; Kobayashi, Hiroya. / PD-L1-specific helper T-cells exhibit effective antitumor responses : New strategy of cancer immunotherapy targeting PD-L1 in head and neck squamous cell carcinoma. In: Journal of Translational Medicine. 2019 ; Vol. 17, No. 1.
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T2 - New strategy of cancer immunotherapy targeting PD-L1 in head and neck squamous cell carcinoma

AU - Hirata-Nozaki, Yui

AU - Ohkuri, Takayuki

AU - Ohara, Kenzo

AU - Kumai, Takumi

AU - Nagata, Marino

AU - Harabuchi, Shohei

AU - Kosaka, Akemi

AU - Nagato, Toshihiro

AU - Ishibashi, Kei

AU - Oikawa, Kensuke

AU - Aoki, Naoko

AU - Ohara, Mizuho

AU - Harabuchi, Yasuaki

AU - Uno, Yuji

AU - Takei, Hidehiro

AU - Celis, Esteban

AU - Kobayashi, Hiroya

PY - 2019/6/20

Y1 - 2019/6/20

N2 - Background: Head and neck squamous cell carcinoma (HNSCC) originates from squamous epithelium of the upper aerodigestive tract and is the most common malignancy in the head and neck region. Among HNSCCs, oropharynx squamous cell carcinoma (OSCC) has a unique profile and is associated with human papillomavirus infection. Recently, anti-programmed cell death-1 monoclonal antibody has yielded good clinical responses in recurrent and/or metastatic HNSCC patients. Therefore, programmed death-ligand 1 (PD-L1) may be a favorable target molecule for cancer immunotherapy. Although PD-L1-expressing malignant cells could be targeted by PD-L1-specific CD8+ cytotoxic T lymphocytes, it remains unclear whether CD4+ helper T lymphocytes (HTLs) recognize and kill tumor cells in a PD-L1-specific manner. Methods: The expression levels of PD-L1 and HLA-DR were evaluated using immunohistochemical analyses. MHC class II-binding peptides for PD-L1 were designed based on computer algorithm analyses and added into in vitro culture of HTLs with antigen-presenting cells to evaluate their stimulatory activity. Results: We found that seven of 24 cases of OSCC showed positive for both PD-L1 and HLA-DR and that PD-L1241-265 peptide efficiently activates HTLs, which showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-dependent manner. Also, an adoptive transfer of the PD-L1-specific HTLs significantly inhibited growth of PD-L1-expressing human tumor cell lines in an immunodeficient mouse model. Importantly, T cell responses specific for the PD-L1241-265 peptide were detected in the HNSCC patients. Conclusions: The cancer immunotherapy targeting PD-L1 as a helper T-cell antigen would be a rational strategy for HNSCC patients.

AB - Background: Head and neck squamous cell carcinoma (HNSCC) originates from squamous epithelium of the upper aerodigestive tract and is the most common malignancy in the head and neck region. Among HNSCCs, oropharynx squamous cell carcinoma (OSCC) has a unique profile and is associated with human papillomavirus infection. Recently, anti-programmed cell death-1 monoclonal antibody has yielded good clinical responses in recurrent and/or metastatic HNSCC patients. Therefore, programmed death-ligand 1 (PD-L1) may be a favorable target molecule for cancer immunotherapy. Although PD-L1-expressing malignant cells could be targeted by PD-L1-specific CD8+ cytotoxic T lymphocytes, it remains unclear whether CD4+ helper T lymphocytes (HTLs) recognize and kill tumor cells in a PD-L1-specific manner. Methods: The expression levels of PD-L1 and HLA-DR were evaluated using immunohistochemical analyses. MHC class II-binding peptides for PD-L1 were designed based on computer algorithm analyses and added into in vitro culture of HTLs with antigen-presenting cells to evaluate their stimulatory activity. Results: We found that seven of 24 cases of OSCC showed positive for both PD-L1 and HLA-DR and that PD-L1241-265 peptide efficiently activates HTLs, which showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-dependent manner. Also, an adoptive transfer of the PD-L1-specific HTLs significantly inhibited growth of PD-L1-expressing human tumor cell lines in an immunodeficient mouse model. Importantly, T cell responses specific for the PD-L1241-265 peptide were detected in the HNSCC patients. Conclusions: The cancer immunotherapy targeting PD-L1 as a helper T-cell antigen would be a rational strategy for HNSCC patients.

KW - Cancer immunotherapy

KW - Head and neck squamous cell carcinoma

KW - Helper T-cells

KW - PD-L1

KW - Tumor-associated antigen

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