Induction of stem-like memory T cells by cancer vaccine is associated with TCR downregulation and correlates to strong antitumor effect

Abstract

To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we have focused on studying the intrinsic attributes of two alpha fetoprotein-specific CD8 T cells (Tet₂₁₂ and Tet₄₉₉). We found that while Tet₄₉₉ survived in vitro re-stimulation and maintained their functions, Tet₂₁₂ underwent exhaustion and apoptosis. In vivo, Tet₄₉₉ generated more expansion than Tet₂₁₂ and stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet₂₁₂ and Tet₄₉₉ correlated to their activation and differentiation state. Compared to Tet₂₁₂, Tet₄₉₉ were in a lower activation state and contained more stem-like memory T cells (Tscm) that could undergo more expansion in vivo. Mechanistically, Tet₄₉₉ TCR was more downregulated than Tet₂₁₂ TCR, which may be responsible for the lower activation and differentiation state of Tet₄₉₉. In contrast to the notion that TCR downregulation dampens T cell antigen reactivity, our data show that it may help T cells maintain their antigen reactivity by halting their activation and differentiation at Tscm stage and by protecting T effector cells from antigen-induced exhaustion and apoptosis. These findings indicate that the focus of cancer vaccination should be on eliciting tumor-specific T cells at earlier differentiation stage including Tscm for better antigen reactivity.