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

L Gattinoni, CA Klebanoff, DC Palmer… - The Journal of …, 2005 - Am Soc Clin Investig
L Gattinoni, CA Klebanoff, DC Palmer, C Wrzesinski, K Kerstann, Z Yu, SE Finkelstein
The Journal of clinical investigation, 2005Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation