| To study mechanisms by which tumors evade host immune responses, we utilized a T cell (DUC18) that specifically destroys a transplantable fibrosarcoma (CMS5) via a neoantigen (tErk) expressed by that tumor line.; CMS5 tumor cells were administered intravenously (i.v.) and subcutaneously (s.c.) to study the impact of surrounding normal tissue on T cell mediated tumor rejection. More T cells were needed to reject CMS5 in the lung than comparable s.c. tumors. This deficiency was abrogated by simultaneous i.v. and s.c. challenge. There was a greater pulmonary DUC18 T cell response in doubly challenged mice, though these cells did not appear phenotypically different from T cells isolated from i.v. challenged mice. Cells from lymph node draining s.c. tumors had greater capacity to stimulate naive DUC18 T cells than those draining pulmonary tumors. Therefore, differences in the ability of various anatomical sites to prime naive T cells can dictate the rejection or outgrowth of a tumor.; To create a spontaneous model of tumor specific T cell responses, we generated a transgenic mouse that expresses the tErk antigen controlled by the mouse mammary tumor virus (MMTV) promoter. These mice were bred to NeuT mice that express the cNeu oncogene under the same promoter. Double transgenic progeny develop spontaneous tErk expressing mammary tumors. Treatment of double transgenic mice with in vitro activated DUC18 T cells slightly delayed the onset of spontaneous mammary tumors. While the in vitro activated T cells are able to delay tumor development, they are rapidly eliminated in antigen-expressing mice. In contrast, naive T cells activated in vivo, in antigen expressing mice, are able to maintain activity. The reasons for this disparity in survival are not clear, but may be the result of the strength of the initial activation signal. Attempts to prolong the survival of the in vitro stimulated DUC18 T cells failed. We also found that activated DUC18 T cells cannot efficiently kill mammary tumor cells directly in vitro, and APC infiltrating these mammary tumors suppress naive T cell proliferation. These data together highlight many layers of immune dysfunction that can allow the outgrowth of malignancies. |
