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

Abstract

To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two α-fetoprotein–specific CD8+ T cells (Tet499 and Tet212) that had different antitumor effects. We found that Tet499 required high antigen doses for re-activation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet212 had a low threshold of re-activation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo, Tet499 cells expanded more than Tet212 upon re-encountering 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 to 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 re-activation 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 re-encounter 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 re-stimulation to generate antitumor effects.

Identification of α‐fetoprotein‐specific T‐cell receptors for hepatocellular carcinoma immunotherapy

“…On the other hand, we found that stemlike memory T cells with naive-like phenotype generated a better antigen response in vivo. (46) In the current study, we found that a significant portion of TCR-T cells were of naive-like phenotype (CD45RA 1 CD62L 1 ) in NSG mice. Whether the CD45RA 1 CD62L 1 cells are more responsive to antigen and thus generate a better antitumor effect on TCR-T cells remains to be studied.…”

“…One recent study found the CD26 hi T cells were more persistent after transfer and generated a potent antitumor effect, which may be the better T‐cell subset for TCR engineering. On the other hand, we found that stem‐like memory T cells with naive‐like phenotype generated a better antigen response in vivo . In the current study, we found that a significant portion of TCR‐T cells were of naive‐like phenotype (CD45RA + CD62L + ) in NSG mice.…”

Impaired T cell proliferation byex vivoBET-inhibition impedes adoptive immunotherapy in a murine melanoma model

“…Furthermore, human studies utilizes non-specific, polyclonal T cell activation to generate T cell grafts for ACT, whereas we investigated antigen-specific CD8 + T cell activation in our study. As TCR affinity affects the ability of CD8 + T cells to differentiate into T scm cells, our results might be influenced by our TCR transgenic model [26]. Lastly, JQ1 improved both CD8 + and CD4 + T cell function and engraftment [15], whereas our model is limited to the study of CD8 + T cells.…”

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

“…The TCR repertoire of naturally primed CD8 + T cells includes mostly TCRs with medium to low affinity, some of which are cross-reactive to autoantigens [32]. Nevertheless, lower affinity TCR may facilitate the priming of long lasting immune memory [33], including stem cells like memory T cells (Tscm). Mysteriously, natural TIL therapy seemed only succeeding in controlling melanoma and Hodgkin's disease but failed in other tumor types with identifiable tumor-associated antigens [34].…”

“…It seems to be that the efficacy of initial tumor control by ACT is associated with high-affinity T cell engraftment, but this may not be true if a long-lasting antitumor T cell persistence is required. Low affinity T cells with the capability becoming stem memory T cells (Tscm) were reported to produce better and long lasting protective effects in mouse model of HCC [33]. Generating long lasting memory T cells including Tscm probably is the holy grail of ACT to reach the goal of long lasting tumor control or eradication.…”