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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IL-15 uncouples T cell proliferation from differentiation and preserves ...
IL-15 uncouples T cell proliferation from differentiation and preserves antitumor efficacy in vivo. Pmel-1 splenocytes were cultured and restimulated weekly in the presence of 1 μM hgp10025-33 and CM containing 30 UI/ml of rhIL-2 (Pmel-1IL-2) or 10 ng/mL rhIL-15 (Pmel-1IL-15). (A) T cells expand similarly in media containing IL-2 and IL-15. Pmel-1IL-2 and pmel-1IL-15 cells were enumerated using trypan blue exclusion at indicated time points. Data shown are representative of 2 independent experiments. (B) IL-15 preserves the expression of lymphoid-homing molecules after multiple in vitro stimulations. Flow cytometry analysis for the expression of the lymphoid-homing molecule CD62L on pmel-1IL-2 and pmel-1IL-15 after 14 and 21 days of culture. Results after gating for CD8+ cells are shown. Data are representative of 2 independent experiments. (C) IL-15 preserves in vivo antitumor efficacy of T cells after multiple in vitro stimulations. 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 pmel-1IL-2 or pmel-1IL-15 cells cultured for 14 and 21 days 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 2 independent experiments. (D) Correlation between CD62L expression on adoptively transferred T cells and slope of tumor growth curve. Results were pooled from 2 independent experiments.