title: Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.
abstract: 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.
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1502, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Gattinoni
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klebanoff
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Palmer
authors.forename: Claudia
authors.initials: C
authors.lastname: Wrzesinski
authors.forename: Keith
authors.initials: K
authors.lastname: Kerstann
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Steven E
authors.initials: SE
authors.lastname: Finkelstein
authors.forename: Marc R
authors.initials: MR
authors.lastname: Theoret
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: 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
chemical_list: D007376:Interleukin-2; D016201:Receptors, Lymphocyte Homing