Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.
T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8+ T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.
Gattinoni
Luca
L
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1502, USA.
Klebanoff
Christopher A
CA
Palmer
Douglas C
DC
Wrzesinski
Claudia
C
Kerstann
Keith
K
Yu
Zhiya
Z
Finkelstein
Steven E
SE
Theoret
Marc R
MR
Rosenberg
Steven A
SA
Restifo
Nicholas P
NP
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D016922:Cellular Senescence / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation
D007376:Interleukin-2; D016201:Receptors, Lymphocyte Homing