Mechanisms underlying tumor resistance to CD8+ T cell-based therapeutic vaccination

Therapeutic vaccinations used to induce CD8+ cytotoxic T lymphocytes (CTLs) and treat firmly established tumors are generally ineffective. To understand the mechanisms underlying the failure of therapeutic vaccinations, we investigated the fate of tumor-specific CD8+ T cells in tumor-bearing mice with or without vaccinations. Our data demonstrate that tumor-specific CD8+ T cells are activated at the early stage of tumor growth, tumor-specific CTL response reaches a maximal level during progressive tumor growth, and tumor-specific CD8+ T cells lose cytolytic function at the late stage of tumor growth. The early-stage therapeutic vaccination induces efficient antitumor activity by amplifying the CTL response, whereas the late-stage therapeutic vaccination is invalid due to tumor-induced dysfunction of CD8+ T cells. However, at the late stage, tumor-specific CD8+ T cells are still present in the periphery. These tumor-specific CD8+ T cells lose cytolytic activity, but retain IFN-gamma secretion function. Furthermore, we demonstrate that tumor-induced tolerance is not due to the initial encounter between tumor-specific CD8+ T cells and tumor cells. The factors developed at the late stage of tumor growth decide peripheral tolerance of tumor-specific CD8+ T cells.; It has been extensively reported that CD4+CD25 + T regulatory (Treg) cells may suppress the effector function of CD8+ T cells. However, in our experiment system, the frequency of peripheral Treg cells is not increased at the late stage of tumor growth, while the tolerance of CD8+ T cells has occurred. After adoptive cotransfer of functional tumor-specific CD8+ T cells from the early-stage mice and CD4+ T cells from the late-stage tolerant mice, tumor-specific CD8+ T cells are not tolerized in tumor-free recipient mice. It suggests that the tolerance of tumor-specific CD8+ T cells might not be due to suppressive CD4+ T cells in our tumor model. Overall, our study suggests that it is important to design a vaccination regimen according to the stages of tumor growth and the functional states of tumor-specific CD8+ T cells. Early-stage vaccinations can efficiently enhance tumor-specific CTL response when CD8+ T cells are functional. More potent strategies are required to reverse the tolerance of CD8+ T cells for late-stage vaccinations to eliminate tumors.