TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity
: 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.
Publisher: Springer Nature
: 2024
Genes and Immunity
: Genes and immunity
: Genes Immun
: 25
: 3
: 188
: 200
: 1466-4879
: 1476-5470
DOI: https://doi.org/10.1038/s41435-024-00274-7
: https://doi.org/10.1038/s41435-024-00274-7
: https://research.utu.fi/converis/portal/detail/Publication/421367232
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.
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