title: Splenectomy promotes indirect elimination of intraocular tumors by CD8+ T cells that is associated with IFNγ- and Fas/FasL-dependent activation of intratumoral macrophages.
abstract: Ocular immune privilege (IP) limits the immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized the immune mechanisms responsible for rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. CD8(+) T cells, IFNγ, and FasL, but not perforin, or TNFα were required for the elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthisis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1(-/-) mice and Fas-defective lpr mice failed to eliminate intraocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras revealed that IFNγR1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (Mϕ) within intraocular tumors in an IFNγ- and Fas/FasL-dependent manner, suggesting an immune cell target of IFNγ and Fas. As depletion of Mϕs limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral Mϕs by CD8(+) T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis, and suggests that immunosuppressive mechanisms that maintain ocular IP interfere with the interaction between CD8(+) T cells and Mϕs to limit the immunosurveillance of intraocular tumors.
authors.affiliation: Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Maxine R
authors.initials: MR
authors.lastname: Miller
authors.affiliation: Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Mandell
authors.affiliation: Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Beatty
authors.affiliation: Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Stephen A K
authors.initials: SA
authors.lastname: Harvey
authors.affiliation: Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania. Graduate Program in Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rizzo
authors.affiliation: Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania. Graduate Program in Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Previte
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Thorne
authors.affiliation: Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. kmckenna@franciscan.edu.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: McKenna
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005134:Eye Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D013156:Splenectomy; D047368:Tumor Burden / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D017471:Receptors, Interferon; D019014:fas Receptor; D007371:Interferon-gamma