title: Cancer cell-binding peptide fused Fc domain activates immune effector cells and blocks tumor growth.
abstract: Therapeutic strategies aiming at mobilizing immune effector cells to kill tumor cells independent of tumor mutational load and MHC expression status are expected to benefit cancer patients. Recently, we engineered various peptide-Fc fusion proteins for directing Fcg receptor-bearing immune cells toward tumor cells. Here, we investigated the immunostimulatory and anti-tumor effects of one of the engineered Fc fusion proteins (WN-Fc). In contrast to the Fc control, soluble WN-Fc-1 fusion protein activated innate immune cells (e.g. monocytes, macrophages, dendritic cells, NK cells), resulting in cytokine production and surface display of the lytic granule marker CD107a on NK cells. An engineered Fc-fusion variant carrying two peptide sequences (WN-Fc-2) also activated immune cells and bound to various cancer cell types with high affinity, including the murine 4T1 breast carcinoma cells. When injected into 4T1 tumor-bearing BALB/c mice, both peptide-Fc fusions accumulated in tumor tissues as compared to other organs such as the lungs. Moreover, treatment of 4T1 tumor-bearing BALB/c mice by means of two intravenous injections of the WN-Fc fusion proteins inhibited tumor growth with WN-Fc-2 being more effective than WN-Fc-1. Treatment resulted in tumor infiltration by T cells and NK cells. These new engineered WN-Fc fusion proteins may be a promising alternative to existing immunotherapies for cancer.
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Mobergslien
authors.affiliation: Department of Pathology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway.
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Pathology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway.
authors.forename: Vlada
authors.initials: V
authors.lastname: Vasovic
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, N-0310 Oslo, Norway.
authors.forename: Mouldy
authors.initials: M
authors.lastname: Sioud
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D007141:Immunoglobulin Fc Fragments / Q000276:immunology* / Q000378:metabolism; D056747:Immunomodulation; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D007141:Immunoglobulin Fc Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins
keywords: Fc-fusion proteins; NK cells; immunostimulation; immunotherapy; innate effector cells