Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination.
Naive and memory CD8(+) T cells can undergo programmed activation and expansion in response to a short T-cell receptor 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 (T(EM)) 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 T(EM) cells. This programmed response was associated with an interval of antigen-independent interferon-gamma (IFN-gamma) release that facilitated the dynamic expression of the major histocompatibility complex class I restriction element H-2D(b) on responding tumor cells, leading to recognition and subsequent tumor lysis. Delaying cell transfer for more than 24 hours after stimulation or infusion of cells deficient in IFN-gamma entirely abrogated the benefit of the programmed response, whereas transfer of cells unable to respond to IFN-gamma had no detriment to antitumor 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.
Klebanoff
Christopher A
CA
Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD, USA. klebanoc@mail.nih.gov
Yu
Zhiya
Z
Hwang
Leroy N
LN
Palmer
Douglas C
DC
Gattinoni
Luca
L
Restifo
Nicholas P
NP
D000818:Animals; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D019496:Cancer Vaccines / Q000378:metabolism*; D002469:Cell Separation; D005434:Flow Cytometry; D005805:Genes, MHC Class I; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D008285:Major Histocompatibility Complex; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology; D010641:Phenotype
D018106:CD28 Antigens; D017252:CD3 Complex; D019496:Cancer Vaccines; D007371:Interferon-gamma