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Kyle C. McKenna, Kelly M. Beatty, Dana M. Previte, Michael Rizzo, Rachel Sikorski, Stephen Thorne; Splenectomy Restores Tumoricidal Activity of CD8+ T cells and Macrophages in Ocular Tumors. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5474.
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© ARVO (1962-2015); The Authors (2016-present)
The purpose of this study was to characterize the requirements for spontaneous rejection of tumors transplanted in the anterior chamber (a.c.) of splenectomized mice as a first step toward identifying how to restore tumoricidal activity within ocular tumors.
P815 or luciferase expressing E.G7-OVA (Luc E.G7) tumors (104 cells) were injected in the a.c. of the eye of wildtype, CD4 depleted, CD8 depleted, B cell deficient (μMT), perforin deficient, IFNγ receptor 1 deficient, or inducible nitric oxide synthase (NOS2) deficient mice that were splenectomized or left untreated prior to tumor challenge. In some experiments intraocular macrophages were depleted by subconjunctival administration of clodronate liposomes. P815 tumor growth was monitored by visual inspection and Luc E.G7 tumor growth was measured by bioluminescent imaging using an IVIS imager. Tumor-specific CD8+ T cells were monitored in vivo by flow cytometry.
P815 and E.G7-OVA tumors grew progressively in the a.c. of nonsplenectomized mice but were rejected in splenectomized mice. Rejection of ocular tumors in splenectomized mice required CD8+ T cells and macrophages. CD4+ T cells were not required as a tumoricidal effector or to provide help to tumor specific CD8+ T cells. The frequency of tumor-specific CD8+ T cells within ocular tumors of splenectomized and nonsplenectomized mice was equivalent as was their expression of granzyme B. The tumoricidal activity of CD8+ T cells in splenectomized mice was perforin independent and required host cell expression of IFNγR1. Nitric oxide (NO) production was not required for rejection of ocular tumors.
These data suggest a model of ocular tumor regression in splenectomized mice in which CD8+ T cells express IFNγ to induce tumoricidal activity within intratumoral macrophages. Previously, we demonstrated that regression of established E.G7-OVA skin tumors after tumor specific CTL transfer therapy required CTL to induce macrophages to produce tumoricidal concentrations of nitric oxide (NO). Surprisingly, rejection of ocular tumors in splenectomized mice did not require NO. These data indicate that while splenectomy restores tumoricidal activity of CD8+ T cells and macrophages within the eye, immune privilege remains at least partially intact as NO production by intraocular macrophages is excluded as a tumoricidal effector mechanism.
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