Adoptive cellular therapy, in which activated tumor-reactive T cells are transferred into lymphodepleted hosts, is a promising cancer treatment option. As activation of T cells decreases IL-7 responsiveness, IL-15 is thought to be the main driver of effector T cell responses in this setting. However, we find that CD8+ T cells activated with IL-12 demonstrate enhanced engraftment in lymphodepleted hosts that is initially dependent on host IL-7 but not IL-15. Mechanistically, enhanced IL-7 responsiveness was conferred by elevated IL-7Ra expression, and importantly, IL-7Ra levels were critical for anti-tumor immunity. Elevated IL-7Ra expression was achievable without IL-12, as polyclonal CD8+ T cells activated with high TCR stimulation depended on T cell IL-7Rα expression and host IL-7 for maximal engraftment. Finally, IL-12 conditioning during the activation of human CD8+ T cells, including TCR-modified T cells generated using a clinically relevant protocol, led to greatly enhanced IL-7Ra expression. Our results demonstrate the importance of the donor IL-7Ra/host IL-7 axis for effector CD8+ T cell engraftment and suggest novel strategies to improve adoptive cellular therapy as a cancer treatment.
- Received April 1, 2015.
- Revision received May 27, 2015.
- Accepted July 2, 2015.
- Copyright © 2015, American Association for Cancer Research.