| Cytotoxic T lymphocytes (CTLs) can reject recent challenges of cancer cells. However, once these cancer cells form solid tissues and become established in the host, CTLs are almost always ineffective at rejecting the tumor burden. In this work, I addressed how established tumors may escape an immune response.; First, I determined whether an antigen induced in a growing tumor elicited an immune response. Whereas tumor-bearing mice did not generate antibodies to the uninduced antigen, tumor-bearing mice generated specific IgG antibodies within three weeks after antigen induction. Compared to the uninduced antigen, CD8+ T cells also responded significantly greater to established tumors in which the antigen was induced to higher levels of expression. Thus, only highly expressed antigens elicited immune responses in tumor-bearing mice.; Second, I examined if the non-malignant stromal cells in the tumor affected the level of antigen expression necessary to induce an immune response. When cancer cells were in suspension and devoid of stroma, T cells responded to and rejected cancer cells expressing different levels of antigen. In contrast, solid tumors expressing low levels of antigen grew progressively, whereas solid tumors expressing high levels of antigen were rejected. Highly expressed antigens were likely crosspresented because immune responses against solid tumors required syngeneic stroma.; Since cross presentation of antigen by the tumor stroma was necessary to induce an immune response, I determined if the tumor stroma was also involved during the effector phase of T cell mediated tumor rejection. The same systemic CTLs rejected established tumors that expressed a high level of antigen but not established tumors that expressed a low level of antigen. Established tumors expressing low levels of antigen escaped rejection as antigen loss variants. The rejection of established tumors likely required T cell recognition of antigen on the tumor stroma because tumors expressing high levels of antigen escaped rejection when the tumor stroma was not capable of crosspresenting the tumor antigen.; Thus, the tumor stroma determines whether the level of antigen is sufficient to induce a CTL response and whether that response can effectively eliminate a genetically heterogeneous tumor. |
