title: The novel C24D synthetic polypeptide inhibits binding of placenta immunosuppressive ferritin to human T cells and elicits anti-breast cancer immunity in vitro and in vivo.
abstract: Immune tolerance mechanisms supporting normal human pregnancy are exploited by breast cancer and other malignancies. We cloned from human placenta and breast cancer cells the novel human immunomodulator named placenta immunosuppressive ferritin (PLIF). PLIF is composed of a ferritin heavy chain-like domain and a novel cytokine-like domain, named C48. Both intact PLIF and C48 inhibit T cell proliferation. Blocking PLIF by specific antibodies in a tolerant breast cancer model in nude mice resulted in tumor cell apoptosis and rejection. This prompted us to study active immune preventive strategies targeting PLIF activity. Currently, we report on the design and synthesis of the novel C24D polypeptide, which inhibits the binding of PLIF to T cells and therefore inhibits the immune suppressive effect of PLIF. The effect of C24D on the generation of anti-breast cancer cytotoxic T lymphocytes (CTLs) was studied in vitro in cultures of MCF-7 (HLA-A2(+)) or T47D (HLA-A2(-)) breast cancer cells incubated with peripheral blood mononuclear cells (PBMCs) from healthy blood donors. We found that C24D treatment exclusively induced development of CTLs. On reactivation by their specific target cells, the CTLs secreted interferon-γ and induced target apoptosis. Anti-MCF-7 CTLs were cross-cytotoxic to MDA-MB-231 (HLA-A2(+)) triple-negative breast cancer but not to T47D. Moreover, C24D treatment in vivo inhibited the growth of MCF-7 tumors engrafted in immune-compromised nude mice transfused with naïve allogeneic human PBMCs. Our results demonstrate that C24D treatment breakdown breast cancer induced tolerance enabling the initiation of effective anti-tumor immune response.
authors.affiliation: Laboratory of Molecular Immunology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel; Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel. Electronic address: inna.solodeev@gmail.com.
authors.forename: Inna
authors.initials: I
authors.lastname: Solodeev
authors.affiliation: Laboratory of Molecular Immunology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel; Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel.
authors.forename: Muayad A
authors.initials: MA
authors.lastname: Zahalka
authors.affiliation: Laboratory of Molecular Immunology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva 49100, Israel; Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel.
authors.forename: Chaya
authors.initials: C
authors.lastname: Moroz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005260:Female; D005293:Ferritins / Q000378:metabolism*; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010088:Oxidoreductases; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D007371:Interferon-gamma; D005293:Ferritins; C454461:FTH1 protein, human; D010088:Oxidoreductases