Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion
Open accessAbstract
Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3–expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4+ T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.
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High expression of Tim-3, CD57, and KLRG-1, in addition to low CD28, is thought to be associated with T cell senescence.
“In addition to low expression of CD28, high expression of Tim-3, CD57, killer cell lectin-like receptor subfamily G, member 1 (KLRG-1) are thought to be associated with T cell senescence [40,60–64](Fig. 2).”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [64]
Similar findings were obtained in patients with melanoma and lymphoma.
“Similar findings were obtained in patients with melanoma [*63] and lymphoma [64].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [64]
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- Authors
- Huang, X., Bai, X., Cao, Y., Wu, J., Huang, M., Tang, D., Tao, S., Zhu, T., Liu, Y., Yang, Y., Zhou, X., Zhao, Y., Wu, M., Wei, J., Wang, D., Xu, G., Wang, S., Ma, D., & Zhou, J.
- Affiliations
- Tongji Hospital (CN)
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
- Corresponding author
- Ma, Ding
- Zhou, Jianfeng
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2010-02-22
- Volume
- 207
- Issue
- 3
- Pages
- 505-520
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2839144
- OpenAlex
- W2121525901
- Cited by
- 156
- References
- 40
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 14 · 2023: 7 · 2022: 11 · 2021: 13 · 2020: 22 · 2019: 7 · 2018: 10 · 2017: 11 · 2016: 6 · 2015: 11 · 2014: 9 · 2013: 12 · 2012: 8
- FWCI
- 4.43
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-03-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- TIM-3, lymphoma progression, immune evasion, CD4+ T cell suppression, Th1 polarization, B-cell lymphoma, tumor angiogenesis, tumor microenvironment, lymphoma dissemination, cancer immunotherapy
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Endothelium, Humans, Immune Tolerance, Immunosuppression Therapy, Immunotherapy, Lymph Nodes, Lymphocyte Activation, Membrane Proteins, Neovascularization, Pathologic, RNA, Messenger, T-Lymphocytes, Transcription, Genetic, CD4-Positive T-Lymphocytes, Antigens, CD, Lymphoma, Large B-Cell, Diffuse, CD8-Positive T-Lymphocytes, Disease Progression, Vascular Endothelial Growth Factor A
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