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To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two α-fetoprotein-specific CD8 + T cells (Tet 499 and Tet 212 ) that had different antitumor effects. We found that Tet 499 required high antigen doses for reactivation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet 212 had a low threshold of reactivation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo , Tet 499 cells expanded more than Tet 212 upon reencountering antigen and generated stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet 212 and Tet 499 cells correlated with their activation and differentiation states. Compared with Tet 212 , the population of Tet 499 cells was less activated and contained more stem-like memory T cells (Tscm) that could undergo expansion in vivo The TCR signaling strength on Tet 499 was weaker than Tet 212 , correlating with more severe Tet 499 TCR downregulation. Weak TCR signaling may halt T-cell differentiation at the Tscm stage during immune priming and also explains why Tet 499 reactivation requires a high antigen dose. Weak TCR signaling of Tet 499 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. Cancer Immunol Res; 5(10); 908-19. ©2017 AACR .

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells