Transferrin Disassociates TCR from CD3 Signaling Apparatus to Promote Metastasis
Immune recognition and activation by the peptide-laden major histocompatibility complex-T cell receptor (TCR)-CD3 complex is essential for anti-tumor immunity. Tumors may escape immune surveillance by dissembling the complex. Here, we report that transferrin, which is overexpressed in patients with liver metastasis, disassociates TCR from the CD3 signaling apparatus by targeting the constant domain (CD) of T cell receptor α (TCRα), consequently suppresses T cell activation, and inhibits anti-metastatic and anti-tumor immunity. In mouse models of melanoma and lymphoma, transferrin overexpression exacerbates liver metastasis, while its knockdown, antibody, designed peptides, and CD mutation interfering with transferrin-TCRα interaction inhibit metastasis. This work reveals a novel strategy of tumor evasion of immune surveillance by blocking the coupling between TCRs and the CD3 signaling apparatus to suppress TCR activation. Given the conservation of CD and transferrin up-regulation in metastatic tumors, the strategy might be a common metastatic mechanism. Targeting transferrin-TCRα holds promise for anti-metastatic treatment.
Authors
- Ruomei Cheng (ORCID: https://orcid.org/0000-0002-0580-2964)
- Qiyu Zhao (ORCID: https://orcid.org/0000-0002-8732-8564)
- Ren Lai (ORCID: https://orcid.org/0000-0002-3123-2336)
- James Mwangi (ORCID: https://orcid.org/0000-0002-5467-9675)
- Qiumin Lu
- Dawit Adisu Tadese (ORCID: https://orcid.org/0000-0003-0293-2760)
- Caiwen Ou (ORCID: https://orcid.org/0000-0002-9515-6125)
- Chenxi Wang (ORCID: https://orcid.org/0000-0002-9547-1547)
- Wenlin Chen (ORCID: https://orcid.org/0000-0001-8986-4064)
- Xiaopeng Tang (ORCID: https://orcid.org/0000-0002-4789-5687)
- Xudong Zhao (ORCID: https://orcid.org/0000-0002-6949-2555)
- Gan Wang (ORCID: https://orcid.org/0000-0003-3199-6309)
- Yuming Wang
Institutions
- Kunming Institute of Zoology (CN)
- Kunming Medical University (CN)
- Sichuan Cancer Hospital (CN)
- Zhujiang Hospital (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Research
- Published
- 2024-12-21
- DOI
- https://doi.org/10.34133/research.0578
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.28
Funders
- Kunming Science and Technology Bureau
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Natural Science Foundation of Yunnan Province
- Yunnan Provincial Science and Technology Department
- Kunming Institute of Zoology, Chinese Academy of Sciences
- National Cancer Institute