TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity

• Published in: Genes and immunity Vol. 25; no. 3; pp. 188 - 200
• Main Authors: Langguth, Miriam, Maranou, Eleftheria, Koskela, Saara A., Elenius, Oskar, Kallionpää, Roosa E., Birkman, Eva-Maria, Pulkkinen, Otto I., Sundvall, Maria, Salmi, Marko, Figueiredo, Carlos R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2024; Nature Publishing Group
• Subjects: 101/1; 13/106; 13/31; 14; 45; 45/47; 45/91; 631/250/21/1293; 631/250/21/324; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cell survival; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Gene Expression; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Human Genetics; Humans; Immune checkpoint; Immunogenicity; Immunology; Immunotherapy; Lymph nodes; Lymphocytes T; Major histocompatibility complex; Melanoma; Melanoma - immunology; Melanoma - metabolism; Metastases; Myeloid Cells - immunology; Myeloid Cells - metabolism; Solid tumors; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Transcriptomics; Tumors
• ISSN: 1476-5470; 1466-4879; 1476-5470
• DOI: 10.1038/s41435-024-00274-7

Immune checkpoint therapies (ICT) for advanced solid tumors mark a new milestone in cancer therapy. Yet their efficacy is often limited by poor immunogenicity, attributed to inadequate priming and generation of antitumor T cells by dendritic cells (DCs). Identifying biomarkers to enhance DC functions in such tumors is thus crucial. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), recognized for its influence on immune cells, has an underexplored relationship with DCs. Our research reveals a correlation between high TIMP1 levels in metastatic melanoma and increased CD8 + T cell infiltration and survival. Network studies indicate a functional connection with HLA genes. Spatial transcriptomic analysis of a national melanoma cohort revealed that TIMP1 expression in immune compartments associates with an HLA-A/MHC-I peptide loading signature in lymph nodes. Primary human and bone-marrow-derived DCs secrete TIMP-1, which notably increases MHC-I expression in classical type 1 dendritic cells (cDC1), especially under melanoma antigen exposure. TIMP-1 affects the immunoproteasome/TAP complex, as seen by upregulated PSMB8 and TAP-1 levels of myeloid DCs. This study uncovers the role of TIMP-1 in DC-mediated immunogenicity with insights into CD8 + T cell activation, providing a foundation for mechanistic exploration and highlighting its potential as a new target for combinatorial immunotherapy to enhance ICT effectiveness.