Crucial role of dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development

Moe Tominaga; Tomofumi Uto; Tomohiro Fukaya; Shuya Mitoma; Dieter Riethmacher; Kunihiko Umekita; Yoshihiro Yamashita; Katsuaki Sato

doi:10.3389/fimmu.2024.1200461

Crucial role of dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development

Front Immunol. 2024 Aug 14:15:1200461. doi: 10.3389/fimmu.2024.1200461. eCollection 2024.

Authors

Moe Tominaga^#^{1

2}, Tomofumi Uto^#^{1

3}, Tomohiro Fukaya^{1

3}, Shuya Mitoma^{1

3}, Dieter Riethmacher⁴, Kunihiko Umekita⁵, Yoshihiro Yamashita², Katsuaki Sato^{1

3

6}

Affiliations

¹ Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
² Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
³ Project for Promotion of Cancer Research and Therapeutic Evolution (P-PROMOTE), Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
⁴ Department of Biomedical Sciences, School of Medicine, Nazarbayev University, Astana, Kazakhstan.
⁵ Division of Respirology, Rheumatology, Infectious Diseases, and Neurology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
⁶ Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.

^# Contributed equally.

Abstract

Dendritic cells (DCs) are known as unique professional antigen (Ag)-presenting cells (APCs) to prime naïve T cells for the initiation of adaptive immunity. While DCs are believed to play a pivotal role in generating anti-tumor T-cell responses, the importance of DCs in the protection from the progression of tumors remains elusive. Here, we show how the constitutive deficiency of CD11c^hi DCs influences the progression of tumors with the use of binary transgenic mice with constitutive loss of CD11c^hi DCs. Constitutive loss of CD11c^hi DCs not only enhances the progression of tumors but also reduces the responses of Ag-specific T cells. Furthermore, the congenital deficiency of CD11c^hi DCs generates the immunosuppressive tumor microenvironment (TME) that correlates with the marked accumulation of myeloid-derived suppressor cells (MDSCs) and the prominent productions of immunosuppressive mediators. Thus, our findings suggest that CD11c^hi DCs are crucial for generating anti-tumor T-cell responses and immunogenic TME to suppress the development of tumors.

Keywords: anti-tumor T-cell responses; dendritic cells; immunosuppressive mediators; myeloid-derived suppressor cells; tumor development; tumor microenvironment.

MeSH terms

Animals
CD11c Antigen / metabolism
Cell Line, Tumor
Dendritic Cells* / immunology
Mice
Mice, Inbred C57BL
Mice, Transgenic*
Myeloid-Derived Suppressor Cells / immunology
Myeloid-Derived Suppressor Cells / metabolism
Neoplasms / immunology
T-Lymphocytes / immunology
Tumor Microenvironment* / immunology

Substances

CD11c Antigen

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a Grant-in-Aid for Scientific Research (B) (KS; 22H02924) and for Scientific Research (C) (TU; 20K07703) from the Ministry of Education, Science and Culture of Japan, the Project for Cancer Research And Therapeutic Evolution (P-CREATE) (KS; 16cm0106307h0001, 17cm0106307h0002, 18cm0106307h0003, 19cm0106307h0004, 20cm0106307h0005, and 21cm0106307h0006) and Project for Promotion of Cancer Research and Therapeutic Evolution (P-PROMOTE) (KS; 22ama221311h0001, 23ama221311h0002, and 24ama221311h0003) from Japan Agency for Medical Research and Development (AMED), the Naito Foundation (KS), Bristol-Myers Squibb Foundation Grants (KS), Daiichi Sankyo Foundation of Life Science (KS), Takeda Science Foundation (TU), Shin-Nihon Foundation of Advanced Medical Research (TU), the Kobayashi Foundation for Cancer Research (TU), SGH Cancer Research Grant (TU), and the Nazarbayev University Faculty-development competitive research grants program (FDCRGP) (DR; 201223FD8819).