title: Tumor escape mutants develop within an immune-privileged environment in the absence of T cell selection.
abstract: The establishment of tumor escape mutants, which can be driven by innate and/or adaptive immune effector cells, presents a significant obstacle in the development of successful tumor immunotherapies. Our study documents that tumors growing within an immune-privileged site within the eye develop a tumor escape phenotype in the absence of selective T cell pressure. P815 tumor cells that are recovered from progressively growing tumors within the anterior chamber of the eye escape elimination when injected into the flanks of a second group of syngeneic DBA/2 mice that were previously immunized against P815 tumor cells. The escape phenotype of eye-derived P815 tumors was stable and permanent when the tumor cells were cultured in vitro. Eye-derived tumor cells recovered from the anterior chamber of CB-17 SCID mice also escaped elimination when injected into the flanks of immunized mice, demonstrating that selective pressure by tumor Ag-specific T cells did not contribute to the development of the escape phenotype. In vitro studies demonstrated that eye-derived tumor cells were not lysed by specific CTL and were unable to restimulate primed Ag-specific T cells. Immune escape of eye-derived tumor cells was not due to down-regulation of either MHC class I or ICAM-1. Our data demonstrate that the immune-privileged environment within the eye induces a tumor escape phenotype that is not driven by selective T cell pressure. We predict that immune escape within the eye is driven by the unique ocular environment that permanently alters gene expression in eye-derived tumor cells.
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Chen
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Uno
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ksander
mesh_terms: D000818:Animals; D000867:Anterior Chamber / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D005134:Eye Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007939:Leukemia L1210; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; D018799:Intercellular Adhesion Molecule-1