Inefficient cross-presentation limits the CD8⁺ T cell response to a subdominant tumor antigen epitope

CD8⁺ T lymphocytes (T_CD8) responding to subdominant epitopes provide alternate targets for the immunotherapy of cancer, particularly when self-tolerance limits the response to immunodominant epitopes. However, the mechanisms that promote T_CD8 subdominance to tumor Ags remain obscure. We investigated the basis for the lack of priming against a subdominant tumor epitope following immunization of C57BL/6 (B6) mice with SV40 large tumor Ag (T Ag)-transformed cells. Immunization of B6 mice with wild-type T Ag-transformed cells primes T_CD8 specific for three immunodominant T Ag epitopes (epitopes I, II/III, and IV) but fails to induce T_CD8 specific for the subdominant T Ag epitope V. Using adoptively transferred T _CD8 from epitope V-specific TCR transgenic mice and immunization with T Ag-transformed cells, we demonstrate that the subdominant epitope V is weakly cross-presented relative to immunodominant epitopes derived from the same protein Ag. Priming of naive epitope V-specific TCR transgenic T_CD8 in B6 mice required cross-presentation by host APC. However, robust expansion of these T_CD8 required additional direct presentation of the subdominant epitope by T Ag-transformed cells and was only significant following immunization with T Ag-expressing cells lacking the immunodominant epitopes. These results indicate that limited cross-presentation coupled with competition by immunodominant epitope-specific T_CD8 contributes to the subdominant nature of a tumor-specific epitope. This finding has implications for vaccination strategies targeting T_CD8 responses to cancer.