Submitted December 2, 2008
Accepted June 20, 2009
Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination
Christopher A. Klebanoff*, Zhiya Yu, Leroy N. Hwang, Douglas C. Palmer, Luca Gattinoni, and Nicholas P. Restifo
Howard Hughes Medical Institute-National Institutes of Health (NIH) Research Scholars Program, Bethesda, MD, United States
Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, MD, United States
* Corresponding author; email: klebanoc{at}mail.nih.gov.
Naive and memory CD8+ T cells can undergo programmed activation and expansion in response to a short TCR stimulus, but the extent to which in vitro programming can qualitatively substitute for an in vivo antigen stimulation remains unknown. We show that self/tumor-reactive effector memory CD8+ T cells (TEM) programmed in vitro either with peptide-pulsed antigen presenting cells or plate bound anti-CD3/anti-CD28 embark on a highly stereotyped response of in vivo clonal expansion and tumor destruction nearly identical to that of vaccine-stimulated TEM cells. This programmed response was associated with an interval of antigen-independent interferon (IFN)-
release that facilitated the dynamic expression of the major histocompatibility complex class I restriction element H-2Db on responding tumor cells, leading to recognition and subsequent tumor lysis. Delaying cell transfer for more than 24h after stimulation or infusion of cells deficient in IFN- entirely abrogated the benefit of the programmed response, whereas transfer of cells unable to respond to IFN- had no detriment to anti-tumor immunity. These findings extend the phenomenon of a programmable effector response to memory CD8+ T cells and have major implications for the design of current adoptive-cell transfer trials.
