Cytotoxic T lymphocytes to an unmutated tumor rejection antigen P1A: Normal development but restrained effector function in vivo

Unmutated tumor antigens are chosen as primary candidates for tumor vaccine because of their expression on multiple lineages of tumors. A critical iss ue is whether unmutated tumor antigens are expressed in normal cells, and i f so, whether such expression imposts special restrictions on cytotoxic T l ymphocyte (CTL) responses. In this study, we use a transgenic approach to s tudy the development and effector function of T cells specific for P1A, a p rototypical unmutated tumor antigen. We report here that although P1A is ex pressed at low levels in normal tissues, including lymphoid tissues, the P1 A-specific transgenic T cells develop normally and remain highly responsive to the P1A antigen. The fact that transgenic expression of P1A antigen in the thymus induces T cell clonal deletion demonstrates that normal hematopo ietic cells can process and present the P1A antigen and that P1A-specific T cells are susceptible to clonal deletion. By inference, P1A-specific T cel ls must have escaped clonal deletion due to low expression of P1A in the th ymus. Interestingly, despite the fact that an overwhelming majority of T ce lls in the T cell receptor for antigen (TCR)-transgenic mice are specific f or P1A, these mice are no more resistant to a P1A-expressing plasmocytoma t han nontransgenic littermates. Moreover, when the same TCR-transgenic mice were challenged simultaneously with B7-1(+) and B7-1(-) tumors, only B7-1() tumors were rejected. Therefore, even though P1A can be a tumor rejection antigen, the effector function of P1A-specific CTL is restrained in vivo. These results have important implications for the strategy of tumor immunot herapy.