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
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
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Research Article Immunology

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

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

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CD62L-selectin identifies CD8+ T cells with superior in vivo antitumor p...
CD62L-selectin identifies CD8+ T cells with superior in vivo antitumor properties. (A) CD62Lhigh subset possesses superior in vivo antitumor properties. WT mice bearing 10-day-old established subcutaneous B16 tumors were sublethally irradiated and left untreated as control or received adoptive transfer of 1 × 106 of pmel-1 CD62Lhigh or CD62Llow cells with exogenous rhIL-2 (36 μg per dose) with or without rFPhgp100 vaccination. Results for tumor area are the mean of measurements from 5 mice per group (± SEM). Data shown are representative of 3 independent experiments. (B and C) CD62Lhigh subset expands vigorously in vivo. (B) Absolute numbers of adoptively transferred CD8+ pmel-1cells in the spleen of tumor-bearing, sublethally irradiated WT mice. Mice were treated with FPhgp100, rhIL-2 (36 μg per dose), and 1 × 106 of pmel-1 CD62Lhigh or CD62Llow cells. Data shown are the mean of 2 mice per group. This experiment was performed twice, with similar results. (C) Percentage of CD8+ pmel-1cells in the tumor. Mice were treated with FPhgp100, rhIL-2 (36 μg per dose), and 1 × 106 of pmel-1 CD62LhighLy5.1 or CD62LlowThy1.1 cells. Data shown are the mean of 2 mice per group. This experiment was performed twice with similar results. (D) CD62L expression is required to maximize the antitumor efficacy of adoptively transferred T cells. WT mice bearing 10-day-old established s.c. B16 tumors were sublethally irradiated and left untreated as control or received adoptive transfer of 1 × 106 one-week-cultured pmel-1 CD62L+/+ cells or pmel-1 CD62L–/– cells in conjunction with rFPhgp100 vaccination and exogenous rhIL-2 (36 μg per dose). Tumor area results are the mean of measurements from 5 mice per group (± SEM). Data shown are representative of 3 independent experiments.