Abstract
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.
Overview
- The study focuses on the immune recognition and activation by the peptide-laden major histocompatibility complex-T cell receptor (TCR)-CD3 complex, essential for anti-tumor immunity.
- The researchers discovered that transferrin, overexpressed in patients with liver metastasis, disassembles TCR from the CD3 signaling apparatus by targeting the constant domain (CD) of T cell receptor α (TCRα), suppressing T cell activation and inhibiting anti-metastatic and anti-tumor immunity.
- The study aims to reveal a novel strategy of tumor evasion of immune surveillance by blocking the coupling between TCRs and the CD3 signaling apparatus to suppress TCR activation, and to identify a potential target for anti-metastatic treatment.
Comparative Analysis & Findings
- The study compared the effects of transferrin overexpression and knockdown on liver metastasis and anti-tumor immunity in mouse models of melanoma and lymphoma.
- Transferrin overexpression exacerbated liver metastasis, while its knockdown, antibody, designed peptides, and CD mutation interfering with transferrin-TCRα interaction inhibited metastasis.
- These findings indicate that targeting transferrin-TCRα may be a potential strategy for anti-metastatic treatment, and that the conservation of CD and transferrin up-regulation in metastatic tumors suggests this mechanism might be common in various metastatic diseases.
Implications and Future Directions
- The study highlights the importance of TCR-CD3 complex in anti-tumor immunity and the role of transferrin in disassembling this complex, leading to tumor evasion.
- To combat this, targeting transferrin-TCRα interactions, such as with designed peptides or antibodies, may be a promising strategy for anti-metastatic treatment.
- Future studies should investigate the conservation of CD and transferrin up-regulation in other metastatic diseases and explore the role of transferrin in tumor evasion in these contexts.