Acquisition of Full Effector Function in Vitro Paradoxically Impairs the in Vivo Antitumor Efficacy of Adoptively Transferred CD8+ T Cells

J Clin Invest. 2005 Jun;115(6):1616-26. doi: 10.1172/JCI24480.

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.

MeSH terms

  • 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

Substances

  • Interleukin-2
  • Receptors, Lymphocyte Homing