Optimal activation of tumor-reactive T cells by selected antigenic peptideanalogues

Many mechanisms have been proposed to explain why immune responses against human tumor antigens are generally ineffective, For example, tumor cells ha ve been shown to develop active immune evasion mechanisms, Another possibil ity is that tumor antigens are unable to optimally stimulate tumor-specific T cells, In this study we have used HLA-A2/Melan-A peptide tetramers to di rectly isolate antigen-specific CD8(+) T cells from tumor-infiltrated lymph nodes. This allowed us to quantify the activation requirements of a repres entative polyclonal yet monospecific tumor-reactive T cell population. The results obtained from quantitative assays of intracellular Ca2+ mobilizatio n, TCR down-regulation, cytokine production and induction of effector cell differentiation indicate that the naturally produced Melan-A peptides are w eak agonists and are clearly suboptimal for T cell activation. In contrast, optimal T cell activation was obtained by stimulation with recently define d peptide analogues, These findings provide a molecular basis for the low i mmunogenicity of tumor cells and suggest that patient immunization with ful l agonist peptide analogues may be essential for stimulation and maintenanc e of anti-tumor T cell responses in vivo.