title: Avirulent Toxoplasma gondii generates therapeutic antitumor immunity by reversing immunosuppression in the ovarian cancer microenvironment.
abstract: Reversing tumor-associated immunosuppression seems necessary to stimulate effective therapeutic immunity against lethal epithelial tumors. Here, we show this goal can be addressed using cps, an avirulent, nonreplicating uracil auxotroph strain of the parasite Toxoplasma gondii (T. gondii), which preferentially invades immunosuppressive CD11c(+) antigen-presenting cells in the ovarian carcinoma microenvironment. Tumor-associated CD11c(+) cells invaded by cps were converted to immunostimulatory phenotypes, which expressed increased levels of the T-cell receptor costimulatory molecules CD80 and CD86. In response to cps treatment of the immunosuppressive ovarian tumor environment, CD11c(+) cells regained the ability to efficiently cross-present antigen and prime CD8(+) T-cell responses. Correspondingly, cps treatment markedly increased tumor antigen-specific responses by CD8(+) T cells. Adoptive transfer experiments showed that these antitumor T-cell responses were effective in suppressing solid tumor development. Indeed, intraperitoneal cps treatment triggered rejection of established ID8-VegfA tumors, an aggressive xenograft model of ovarian carcinoma, also conferring a survival benefit in a related aggressive model (ID8-Defb29/Vegf-A). The therapeutic benefit of cps treatment relied on expression of IL-12, but it was unexpectedly independent of MyD88 signaling as well as immune experience with T. gondii. Taken together, our results establish that cps preferentially invades tumor-associated antigen-presenting cells and restores their ability to trigger potent antitumor CD8(+) T-cell responses. Immunochemotherapeutic applications of cps might be broadly useful to reawaken natural immunity in the highly immunosuppressive microenvironment of most solid tumors.
authors.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Baird
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Fox
authors.forename: Kiah L
authors.initials: KL
authors.lastname: Sanders
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Lizotte
authors.forename: Juan R
authors.initials: JR
authors.lastname: Cubillos-Ruiz
authors.forename: Uciane K
authors.initials: UK
authors.lastname: Scarlett
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
authors.forename: Steven
authors.initials: S
authors.lastname: Fiering
authors.forename: David J
authors.initials: DJ
authors.lastname: Bzik
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016052:Protozoan Vaccines; D013154:Spleen / Q000276:immunology / Q000473:pathology; D014122:Toxoplasma / Q000276:immunology*; D047368:Tumor Burden / Q000276:immunology; D019139:Tumor Escape; D059016:Tumor Microenvironment / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D039521:CD11c Antigen; D019496:Cancer Vaccines; D016207:Cytokines; D016052:Protozoan Vaccines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A