The long-term goal of our research is to develop a tumor cell vaccine that eliminates tumors from immune privileged sites within the eye, and provides long-term protection from recurring metastatic tumors. We developed a CD80 + IL-12 expressing vaccine that successfully activated tumor antigen-specific T cells. Mice immunized with this vaccine were protected from a second challenge with wild type tumors in non-immune privileged sites, such as the flank. Surprisingly, this vaccine was unable to eliminate completely even a small number of tumor cells injected into the immune privileged anterior chamber of the eye. Although immune privilege within the eye is maintained by multiple mechanisms, our experiments revealed a previously unrecognized component of immune privilege. Tumor cells growing within the eye acquire an """"""""escape mutant"""""""" phenotype that allows them to evade immune elimination after they are removed from the privileged site and placed into a non-privileged site. Tumor escape in vivo coincides with a reduced lysis by specific CD8+ cytotoxic T cells in vitro. We hypothesize the ocular environment induces """"""""escape mutant"""""""" tumor cells that avoid immune elimination by antigen-specific T cells. The hypothesis will be tested by four specific aims that: (1) identify and characterize the escape mutant tumor phenotype induced within the eye, (2) determine whether CD8+ T cell proliferation and cytokine secretion is reduced in response to escape mutant tumor cells, (3) determine the mechanism used by eye-derived tumor cells to escape immune elimination, and (4) determine how the eye induces escape mutant tumor cells. Data from a number of laboratories indicates that spontaneous human tumors (that develop outside the eye) establish their own immune privileged environment. In general, the eye and spontaneous non-ocular tumors share similar mechanisms in evading the immune system. Therefore, it seems reasonable to expect the mechanisms responsible for inducing escape mutant tumor cells within the eye may also be used by tumors that develop outside the eye. This is particularly important, since the development of escape mutants is a major impediment to creating effective cancer immunotherapies. Therefore, we believe the study of the escape mutant phenotype within the eye has great potential for providing important insights into the creation of successful anticancer immunotherapies.
| Gregory, Meredith S; Saff, Rebecca R; Marshak-Rothstein, Ann et al. (2007) Control of ocular tumor growth and metastatic spread by soluble and membrane Fas ligand. Cancer Res 67:11951-8 |
| Gregory, Meredith S; Koh, Sean; Huang, Eric et al. (2005) A novel treatment for ocular tumors using membrane FasL vesicles to activate innate immunity and terminate immune privilege. Invest Ophthalmol Vis Sci 46:2495-502 |
| Gregory, Meredith S; Repp, Amanda C; Holhbaum, Andreas M et al. (2002) Membrane Fas ligand activates innate immunity and terminates ocular immune privilege. J Immunol 169:2727-35 |
