Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer

Takuma Matoba; Masaki Imai; Naganari Ohkura; Daisuke Kawakita; Kei Ijichi; Tatsuya Toyama; Akimichi Morita; Shingo Murakami; Shimon Sakaguchi; Sayuri Yamazaki

doi:10.1002/ijc.32024

Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer

Int J Cancer. 2019 Jun 1;144(11):2811-2822. doi: 10.1002/ijc.32024. Epub 2018 Dec 16.

Authors

Takuma Matoba^{1

2}, Masaki Imai¹, Naganari Ohkura^{3

4}, Daisuke Kawakita², Kei Ijichi^{2

5}, Tatsuya Toyama⁶, Akimichi Morita⁷, Shingo Murakami^{2

8}, Shimon Sakaguchi³, Sayuri Yamazaki¹

Affiliations

¹ Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
² Department of Oto-rhino-laryngology and Head-and-neck-surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
³ Department of Experimental Immunology, World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
⁴ Department of Frontier Research in Tumor Immunology, Center of Medical Innovation and Translational Research, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁵ Akaike Oto-rhino-laryngology and Head-and-neck-surgery Clinic, Nisshin, Japan.
⁶ Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
⁷ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
⁸ Department of Oto-rhino-laryngology, Nagoya City East Medical Center, Nagoya, Japan.

PMID: 30485427
DOI: 10.1002/ijc.32024

Abstract

FOXP3⁺ regulatory T (Treg) cells suppress anti-tumor immunity. The suppression of Treg cells is regulated by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA-4 on the cell surface (surface-CTLA-4⁺ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface-CTLA-4⁺ and surface-CTLA-4^- Treg cells infiltrating human head and neck cancer tissues revealed that surface-CTLA-4⁺ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface-CTLA-4⁺ Treg cells were PD-1⁺ , actively proliferated and associated with CD45RA^- FOXP3^high Treg cells with strong suppressive function. Thus, surface-CTLA-4⁺ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface-CTLA-4⁺ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer.

Keywords: RNA sequencing; human head and neck cancer; regulatory T cells; surface expression of CTLA-4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Biopsy
CTLA-4 Antigen / immunology
CTLA-4 Antigen / metabolism*
Cell Proliferation*
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / immunology
Head and Neck Neoplasms / immunology*
Head and Neck Neoplasms / pathology
Head and Neck Neoplasms / surgery
Humans
Male
Middle Aged
Sequence Analysis, RNA
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Tumor Microenvironment / immunology*

Substances

CTLA-4 Antigen
CTLA4 protein, human