The antitumor effects of vaccine-activated CD8⁺ T cells associate with weak TCR signaling and induction of stem-like memory T cells

To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two a-feto-protein–specific CD8⁺ T cells (Tet₄₉₉ and Tet₂₁₂) that had different antitumor effects. We found that Tet₄₉₉ required high antigen doses for reactivation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet₂₁₂ had a low threshold of reactivation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo, Tet₄₉₉ cells expanded more than Tet₂₁₂ upon reencountering antigen and generated stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet₂₁₂ and Tet₄₉₉ cells correlated with their activation and differentiation states. Compared with Tet₂₁₂, the population of Tet₄₉₉ cells was less activated and contained more stem-like memory T cells (Tscm) that could undergo expansion in vivo. The TCR signaling strength on Tet₄₉₉ was weaker than Tet₂₁₂, correlating with more severe Tet₄₉₉ TCR downregulation. Weak TCR signaling may halt T-cell differentiation at the Tscm stage during immune priming and also explains why Tet₄₉₉ reactivation requires a high antigen dose. Weak TCR signaling of Tet₄₉₉ cells in the effector stage will also protect them from exhaustion and apoptosis when they reencounter persistent antigen in tumor lesion, which generates antitumor effects. Further investigation of TCR downregulation and manipulation of TCR signaling strength may help design cancer vaccines to elicit a mix of tumor-specific CD8⁺ T cells, including Tscm, capable of surviving antigen restimulation to generate antitumor effects.