Splenectomy Promotes Indirect Elimination of Intraocular Tumors by CD8+ T Cells That Is Associated with IFNγ- and Fas/FasL-Dependent Activation of Intratumoral Macrophages

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, IFN gamma, and FasL, but not perforin, or TNF alpha were required for the elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthisis). IFNg and FasL did not target tumor cells directly as the majority of SPLNX IFN gamma R1(-/-) mice and Fas-defective lpr mice failed to eliminate intraocular E.G7-OVA tumors that expressed Fas and IFN gamma R1. Bone marrow chimeras revealed that IFN gamma R1 and Fas expression on immune cells was most critical for rejection, and SPLNX increased the frequency of activated macrophages (M phi) within intraocular tumors in an IFN gamma- and Fas/FasL-dependent manner, suggesting an immune cell target of IFN gamma and Fas. As depletion of M phi s limited CD8 T cell-mediated rejection of intraocular tumors in SPLNX mice, our data support a model in which IFN gamma- and Fas/FasL-dependent activation of intratumoral M phi s 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 Mfs to limit the immunosurveillance of intraocular tumors. (C) 2014 AACR.