title: Human survivin and Trypanosoma cruzi calreticulin act in synergy against a murine melanoma in vivo.
abstract: Immune-based anti-tumor or anti-angiogenic therapies hold considerable promise for the treatment of cancer. The first approach seeks to activate tumor antigen-specific T lymphocytes while, the second, delays tumor growth by interfering with blood supply. Tumor Associated Antigens are often employed to target tumors with therapeutic drugs, but some are also essential for tumor viability. Survivin (Surv) is a member of the inhibitor of apoptosis protein family that is considered a Tumor Associated Antigen important for cancer cell viability and proliferation. On the other hand, Trypanosoma cruzi (the agent of Chagas' disease) calreticulin (TcCRT) displays remarkable anti-angiogenic properties. Because these molecules are associated with different tumor targets, we reasoned that immunization with a Surv-encoding plasmid (pSurv) and concomitant TcCRT administration should generate a stronger anti-tumor response than application of either treatment separately. To evaluate this possibility, C57BL/6 mice were immunized with pSurv and challenged with an isogenic melanoma cell line that had been pre-incubated with recombinant TcCRT (rTcCRT). Following tumor cell inoculation, mice were injected with additional doses of rTcCRT. For the combined regimen we observed in mice that: i). Tumor growth was impaired, ii). Humoral anti-rTcCRT immunity was induced and, iii). In vitro rTcCRT bound to melanocytes, thereby promoting the incorporation of human C1q and subsequent macrophage phagocytosis of tumor cells. These observations are interpreted to reflect the consequence of the following sequence of events: rTcCRT anti-angiogenic activity leads to stress in tumor cells. Murine CRT is then translocated to the external membrane where, together with rTcCRT, complement C1 is captured, thus promoting tumor phagocytosis. Presentation of the Tumor Associated Antigen Surv induces the adaptive anti-tumor immunity and, independently, mediates anti-endothelial cell immunity leading to an important delay in tumor growth.
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Aguilar-Guzmán
authors.affiliation: Laboratory of Cellular Communication, Center for Molecular Studies of the Cell, Program of Cell and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Lobos-González
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rosas
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Vallejos
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Cristián
authors.initials: C
authors.lastname: Falcón
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sosoniuk
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Francisca
authors.initials: F
authors.lastname: Coddou
authors.affiliation: Laboratory of Cellular Communication, Center for Molecular Studies of the Cell, Program of Cell and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Lisette
authors.initials: L
authors.lastname: Leyton
authors.affiliation: Program of Anatomy and Developmental Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Lemus
authors.affiliation: Laboratory of Cellular Communication, Center for Molecular Studies of the Cell, Program of Cell and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Andrew F G
authors.initials: AF
authors.lastname: Quest
authors.affiliation: Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Arturo
authors.initials: A
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015922:Complement C1q / Q000378:metabolism; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000187:drug effects; D007114:Immunization; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000628:therapy; D010587:Phagocytosis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000473:pathology; D000077022:Survivin; D014349:Trypanosoma cruzi / Q000378:metabolism*
chemical_list: C107489:BIRC5 protein, human; D037282:Calreticulin; D051034:Inhibitor of Apoptosis Proteins; D011994:Recombinant Proteins; D000077022:Survivin; D015922:Complement C1q
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