Transferrin Disassociates TCR from CD3 Signaling Apparatus to Promote Metastasis
Ruomei Cheng,
Xiaopeng Tang,
Qiyu Zhao,
Yuming Wang,
Wenlin Chen,
Gan Wang,
Chenxi Wang,
James Mwangi,
Qiumin Lu,
Dawit Adisu Tadese,
Xudong Zhao,
Caiwen Ou,
Ren Lai
Affiliations
Ruomei Cheng
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Xiaopeng Tang
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Qiyu Zhao
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Yuming Wang
Department of Clinical Laboratory,
The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650108, China.
Wenlin Chen
Third Department of Breast Surgery, Peking University Cancer Hospital Yunan, The Third Affiliated Hospital of Kunming Medical University,
Yunnan Cancer Hospital, Kunming, Yunnan 650118, China.
Gan Wang
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Chenxi Wang
Third Department of Breast Surgery, Peking University Cancer Hospital Yunan, The Third Affiliated Hospital of Kunming Medical University,
Yunnan Cancer Hospital, Kunming, Yunnan 650118, China.
James Mwangi
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Qiumin Lu
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Dawit Adisu Tadese
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
Xudong Zhao
Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models, Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-Related Molecular Network, West China Hospital,
Sichuan University, Chengdu, Sichuan 610041, China.
Caiwen Ou
Department of Cardiology and Laboratory of Heart Center, Zhujiang Hospital, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease,
Southern Medical University, Guangzhou, Guangdong 510515, China.
Ren Lai
Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Sino-African Joint Research Center, and New Cornerstone Science Laboratory, Kunming Institute of Zoology,
The Chinese Academy of Sciences, Kunming, Yunnan 650201, China.
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.
