Immunity in a self/non-self antigen model of cancer

In human cancers, most tumor antigens to which immune responses have been identified are also expressed on normal tissues and thus can be thought of as self-antigens. While the underlying requirements for directing successful immunotherapies against cancer expressed antigens remains largely unclear, recent lines of experimentation have shown that some of these self-antigens that are expressed on isolated normal tissues (e.g. differentiation antigens) can stimulate significant anti-tumor responses. So far, these studies have been restricted to the situation in which a particular antigen has restricted peripheral expression. We have hypothesized that a self-antigen that does not exhibit tissue restriction, but is expressed at considerably higher levels on tumor cells than other tissues may similarly serve as a therapeutic target for antigen specific immunotherapy. This thesis reports on the development of a novel cancer model in which immune responses against a model tumor antigen can be compared under conditions where the protein is clearly foreign versus that in which it is expressed broadly on many self tissues, but at low levels compared with the tumor cells. We have done this through the use of an antigen transfected onto a tumor cell line used with the corresponding antigen transgene-expressing mice. Within this model, immunization with either irradiated antigen expressing tumor cells or antigen expressing virus is sufficient to generate specific protective immune responses in normal mice (where the antigen is not expressed). Similar responses were not observed in transgenic mice but could be achieved if mice first received adoptive transfer of naïve whole splenic populations from normal mice. These results suggest that specific naive T cells when supplied ex vivo, can be stimulated to protect against tumor challenges despite the presence of lower levels of the antigen on multiple tissues within the transgenic mice. Importantly, no obvious indications of autoimmune disease were apparent in the protected transgenic mice, suggesting that successful adoptive therapy can be achieved using auto-reactive T cells specific for an antigen that is differentially expressed between tumor and multiple self tissues