Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells

• Published in: The Journal of clinical investigation 2005-06, Vol.115 (6), p.1616-1626
• Main Authors: Gattinoni, Luca, Klebanoff, Christopher A, Palmer, Douglas C, Wrzesinski, Claudia, Kerstann, Keith, Yu, Zhiya, Finkelstein, Steven E, Theoret, Marc R, Rosenberg, Steven A, Restifo, Nicholas P
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - immunology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - transplantation; Cell Proliferation; Cell Survival - immunology; Cellular Senescence - immunology; Immunotherapy, Adoptive; Interleukin-2 - biosynthesis; Lymphocyte Activation - immunology; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Mice; Receptors, Lymphocyte Homing - biosynthesis; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - transplantation
• ISSN: 0021-9738
• DOI: 10.1172/JCI24480

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.