SVR Angiosarcomas can be Rejected by CD4 Costimulation Dependent and CD8 Costimulation Independent Pathways
We wished to determine whether virally-induced endothelial tumors are rejected by CD4 and CD8 lymphocytes, and whether there are differences in requirements for costimulation in the rejection of these tumors by lymphocyte subsets.
We have developed a model of endothelial tumorigenesis through the sequential introduction of SV40 large T antigen and oncogenic H-ras into endothelial cells. These cells (SVR cells) form highly aggressive angiosarcomas in immunocompromised mice, but do not grow in syngeneic C57BL/6 mice. Using both acute blockade with systemic administration of antibodies and mice genetically deficient in the costimulatory molecules CD28, CD40, and CD40L, we have delineated the requirements of costimulation required to reject this virally-induced endothelial tumor.
Control of SVR angiosarcoma is mediated through T lymphocytes, and both CD4 and CD8 lymphocytes are capable of controlling SVR angiosarcoma growth in vivo. Mice genetically deficient in CD28, CD40, and CD40L were able to reject SVR tumors, but depletion of these mice of CD8, but not CD4 cells led to rapid tumor growth. This data suggests that CD4 mediated rejection has a greater dependence of costimulation than CD8 mediated rejection. Surprisingly, acute depletion of costimulatory molecules in immunocompetent C57BL/6 mice led to rapid tumor growth.
Significant differences exist in the immune status of mice acutely depleted of costimulatory molecules versus genetically deficient mice. Our results suggest that acute depletion is more immunosuppressive than genetic depletion. Humans who undergo costimulatory blockade may require periodic surveillance for virally-induced tumors.
JLA was supported in part by the American Skin Association and grants AR02030, AR44947, and RO1AR47901 from the National Institutes of Health. AB, MD, SC, and CL were supported in part by grants DK50762, DK/AI 40519, AI44644, and P30AR42687 (Emory Skin Disease Research Core Center Grant) from the National Institutes of Health, EEC Award 9731643 from the National Science Foundation, and the Carlos and Marguerite Mason Trust.
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