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

Luca Gattinoni, Christopher A. Klebanoff, Douglas C. Palmer, Claudia Wrzesinski, Keith Kerstann, Zhiya Yu, Steven E. Finkelstein, Marc R. Theoret, Steven A. Rosenberg, Nicholas P. Restifo

Research output: Contribution to journalArticle

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 immuno therapy. 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.

Original languageEnglish (US)
Pages (from-to)1616-1626
Number of pages11
JournalJournal of Clinical Investigation
Volume115
Issue number6
DOIs
StatePublished - Jun 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Gattinoni, L., Klebanoff, C. A., Palmer, D. C., Wrzesinski, C., Kerstann, K., Yu, Z., Finkelstein, S. E., Theoret, M. R., Rosenberg, S. A., & Restifo, N. P. (2005). Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. Journal of Clinical Investigation, 115(6), 1616-1626. https://doi.org/10.1172/JCI24480