title: Ovarian cancer progression is controlled by phenotypic changes in dendritic cells.
abstract: We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity.
authors.affiliation: Immunology Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Uciane K
authors.initials: UK
authors.lastname: Scarlett
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.forename: Adam M
authors.initials: AM
authors.lastname: Rauwerdink
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fields
authors.forename: Ximena
authors.initials: X
authors.lastname: Escovar-Fadul
authors.forename: Jason
authors.initials: J
authors.lastname: Baird
authors.forename: Juan R
authors.initials: JR
authors.lastname: Cubillos-Ruiz
authors.forename: Ana C
authors.initials: AC
authors.lastname: Jacobs
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gonzalez
authors.forename: John
authors.initials: J
authors.lastname: Weaver
authors.forename: Steven
authors.initials: S
authors.lastname: Fiering
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001483:Base Sequence; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D015232:Dinoprostone / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016158:Genes, p53; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D010051:Ovarian Neoplasms / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D015232:Dinoprostone