The immune system plays a critical role in protecting the body from cancer by recognizing and eliminating abnormal cells before they can develop into tumors. This process relies on T cells that can recognize tumor-derived antigens presented by dendritic cells (DCs). However, tumor cells frequently evade immune surveillance and establish immune tolerance through various mechanisms, most of which are thought to occur within the tumor microenvironment. In contrast, whether such tolerance is also established in the thymus as central tolerance to tumor antigens remains unclear.
To address this knowledge gap, researchers from Chiba University, Japan, have discovered a mechanism by which tumors can manipulate the thymus, the organ that trains immune cells, to tolerate their presence rather than fight them. The team was led by Professor Motoko Y. Kimura and first author Dr. Yangsong Wang, both from the Graduate School of Medicine at Chiba University . The study was published in the journal Science Advances on July 23, 2026.
The thymus is an organ where T cells develop and are trained to distinguish self and non-self. The study found that as tumors grow, plasmacytoid DCs (pDCs) accumulate in the thymus and help transport tumor antigens there, triggering the elimination of developing T cells capable of recognizing tumors.
"Our findings suggest that tumors can hijack the physiological machinery of central tolerance to induce systemic immune unresponsiveness against themselves," says Prof. Kimura.
The team made this discovery by studying tumor-bearing mice, where they observed that pDC accumulation began within 2 weeks of tumor implantation and persisted as the tumors continued to grow. They found that the migration of pDCs to the thymus is regulated by a chemokine receptor called CCR9. In mice lacking CCR9, the accumulation of thymic pDCs during tumor progression was largely prevented, indicating that CCR9 is required for this process.
They identified two distinct pDC populations that contribute to this immune evasion. One population originated from common dendritic cell progenitors (CDP-pDCs), while the other arose from common lymphoid progenitors (CLP-pDCs).
CDP-pDCs carry tumor-derived antigens from the tumor to the thymus, where they are presented to developing T cells. As part of its normal training process, the thymus eliminates T cells that react to these antigens. This removes T cells that could otherwise recognize and attack the tumor, reducing anti-tumor immune responses. Meanwhile, CLP-pDCs release IFN-α within the thymus, where they alter the thymic environment, suppressing the production of new T cells and further weakening anti-tumor immunity.
Importantly, the researchers found that disrupting CCR9 could interfere with this immune tolerance mechanism. Mice lacking CCR9 developed smaller tumors and maintained the tumor-specific CD8+ T cell population, indicating a stronger anti-tumor immune response.
"Our findings reveal a previously unrecognized mechanism of tumor immune evasion through manipulating thymic function, and identify CCR9 as a potential therapeutic target in cancer immunotherapy. By blocking the migration of tumor antigen-carrying pDCs from tumors to the thymus, it may be possible to enhance anti-tumor immunity and improve responses to existing treatments such as immune checkpoint inhibitors," says Dr. Wang.
The findings may have implications beyond cancer. The researchers note that chronic or dormant infections that persist in the body for long periods could potentially exploit similar thymic tolerance pathways to evade immune responses.
Looking ahead, the team suggests that future therapies could combine immune-activating treatments with approaches that block thymic tolerance mechanisms. Such approaches could potentially enhance immune responses against cancer and chronic infections, improving long-term treatment outcomes.
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About Professor Motoko Y. Kimura from Chiba University, Japan
Dr. Motoko Y. Kimura is a Professor at Chiba University whose research focuses on T cell development, differentiation, and function. Her laboratory of Experimental Immunology investigates the fundamental mechanisms of T cell-mediated immunity, including how T cells develop in the thymus, maintain immune tolerance, and contribute to autoimmune diseases, inflammatory disorders, and cancer. In addition to basic immunology research, the laboratory pursues the development of new cancer immunotherapies based on insights gained from studying T cell biology. Prof. Kimura hopes her research will reveal fundamental principles of life and ultimately contribute to the treatment of human diseases.
Additional information about the Experimental Immunology Laboratory
Funding:
This study was supported by the Ministry of Education, Culture, Sports, Science, and Technology (MEXT Japan) through Grant-in-Aid for Early-Career Scientists (24K18461), Grant-in-Aid for Scientific Research (B) (20H03464, 24K02259), Grant-in-Aid for Scientific Research (S) (19H05650), Grant-in-Aid for Scientific Research (C) (21K07234), Challenging Research (Exploratory) (20K21537, 18K19466), and Transformative Research Areas (A) (22H05189). Additional support was provided by the Leading Graduate School Program from Chiba University, the Daiichi Sankyo Foundation of Life Science, the Astellas Foundation for Research on Metabolic Disorders, the Uehara Memorial Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Sumitomo Foundation, the Takeda Science Foundation, and the IAAR Research Support Program from Chiba University.
AMED_P-CREATE (Project for Cancer Research and Therapeutic Evolution) 19cm0106339, 21cm0106372: Study of new cancer immunotherapy development to target CD69. AMED_PRIME 21gm6310024: Understanding of the biological phenomena and responses at the early life stages to improve the quality of health and medical care. AMED 223fa627003 Japan Initiative for World-leading Vaccine Research and Development Centers, SCARDA-related and other programs: Chiba University "Synergy Institute for Futuristic Mucosal Vaccine Research and Development."
Reference:
Title of original paper: Distinct thymic pDC populations promote tumor immune tolerance through complementary mechanisms
Authors: Yangsong Wang,1 Ryo Koyama-Nasu,1 Yukihiro Endo,1 Ichita Hasegawa,1 Atsushi Onodera,2,3 Mingyu Chen,4 Kiyoshi Hirahara,5,6 Shinichiro Motohashi,7 Toshinori Nakayama8, and Motoko Y. Kimura1,6
Affiliations:
1Department of Experimental Immunology, Graduate School of Medicine, Chiba University
2Institute for Advanced Academic Research (IAAR), Chiba University
3Research Institute of Disaster Medicine, Chiba University
4Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science
5Department of Immunology, Graduate School of Medicine, Chiba University
6Chiba University, Synergy Institute for Futuristic Mucosal Vaccine Research and
Development (cSIMVa)
7Department of Medical Immunology, Graduate School of Medicine, Chiba University
8Deceased.
Journal: Science Advances
DOI: https://doi.org/10.1126/sciadv.adx9864
