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Maxine Miller, Jonathan Mandell, Kelly Beatty, Michael Rizzo, Dana M Previte, Stephen Thorne, Kyle C McKenna; Spontaneous Intraocular Tumor Regression Requires CD8+ T cells, IFNγ, CD95FasL, and nontumor stroma expression of IFNγR1 and CD95Fas. Invest. Ophthalmol. Vis. Sci. 2014;55(13):89.
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© ARVO (1962-2015); The Authors (2016-present)
To determine immune mechanisms responsible for spontaneous rejection of intraocular tumors in splenectomized (SPLNX) mice.
Ocular tumor burden was monitored by visual inspection or by bioluminescent imaging (BLI) in wild-type and immunodeficient mice that were SPLNX or received a mock surgery prior to injection with P815 or luciferase expressing E.G7-OVA (Luc-E.G7) in the anterior chamber (a.c.) of the eye. Naïve OVA-specific OT-I T cells were transferred into mice prior to ocular Luc-E.G7 tumor challenge and IFNγ expression by OT-I T cells in draining lymph nodes and tumors was evaluated.
P815 or Luc-E.G7 tumors that normally grew progressively when transplanted in the a.c. were rejected in SPLNX mice. CD8+ T cells, IFNγ, and CD178/FasL but not perforin or TNFα, were required for ocular tumor elimination. Although Luc-E.G7 tumors expressed IFNγreceptor (IFNγR1) and CD95/Fas, IFNγ and FasL targeted nontumor stroma as the majority of SPLNX IFNγR1-/- and Fas deficient lpr mice failed to eliminate ocular tumors. Bone marrow chimeras revealed that IFNγR1 expression on immune cells in ocular tumors was most critical. Depletion of phagocytic cells in ocular tumors, via administration of clodronate liposomes, in SPLNX mice significantly reduced rejection suggesting that tumor associated CD11b+ myeloid cells may be a cellular target for IFNγ. Interestingly, intraocular tumor growth in both control and SPLNX mice primed tumor specific IFNγ+ CD8+ T cells in lymph nodes that infiltrated ocular tumors. Hence, IFNγ expression was alone insufficient to promote tumor elimination.
CD8+ T cells eliminate ocular tumors indirectly by targeting immune cells within the tumor stroma via IFNγ. Splenectomy may terminate ocular immune privilege by restoring the interplay between CD8+ T cells and CD11b+ myeloid cells within ocular tumors through Fas/FasL interactions.
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