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ISSN 打印: 1040-8401
ISSN 在线: 2162-6472

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DOI: 10.1615/CritRevImmunol.v21.i1-3.150
34 pages

T-Cell Adoptive Therapy of Tumors: Mechanisms of Improved Therapeutic Performance

Liaomin Peng
Center for Surgery Research, FF-50, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195
Peter A. Cohen
Center for Surgery Research, NE6-307, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Jorgen Kjaergaard
Center for Surgery Research, Cleveland Clinic Foundation, Cleveland, OH
Gregory E. Plautz
Center for Surgery Research, FF-50, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195
James H. Finke
Department of Immunology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA, and the Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Gary K. Koski
Division of Basic Sciences, Center for Cancer Research, National Cancer Institute at Frederick, Frederick MD 21702-1201
Brian J. Czerniecki
Department of Surgery and Harrison Surgical Research Center, University of Pennsylvania, 4th Floor Silverstein, 3400 Spruce Street, Philadelphia, PA 19104
Suyu Shu
Center for Surgery Research, NE6-307, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA

ABSTRACT

The T cells of many cancer patients are naturally sensitized to tumor-associated antigens (Ag), or they can readily be sensitized with vaccine maneuvers. In melanoma patients, the adoptive transfer of such T cells can often be causally linked to the objective regression of established tumors. So far, few patients have shown sustained clinical benefit from such therapy, but preclinical mouse studies have now clearly delineated the hurdles that must be overcome to render T-cell–based antitumor therapy effective. Contrary to earlier expectations, it is now established that remarkably potent CD4+ and CD8+ pre-effector T cells are naturally sensitized even in mice bearing progressive, weakly immunogenic tumors. However, such T cells often display signal transduction impairments as a consequence of the tumor environment, which limit their acquisition of optimal effector function. Extracorporealization and culture of these tumor-sensitized T cells with appropriate activation stimuli not only restores normal signal transduction, but also confers resolute effector activity that can often sustain tumor rejection upon reinfusion. In mouse studies, the L-selectinlow fraction of T cells in tumor-draining lymph nodes (TDLN) constitutes the potent pre-effector population and comprises both CD4+ and helper-independent CD8+ T cells. Appropriate in vitro activation confers an apparently unrestricted trafficking capacity to this fraction, and even the ability to proliferate within the tumor bed, leading to unprecedented tumor rejection at anatomic sites (e.g., subcutaneous and intracranial) that were historically refractory to such treatment. Such results underscore the surprising capacity of appropriately activated effector T cells to withstand the immunosuppressive, tolerogenic, and apoptotic influences of the typical tumor environment. Given the increasingly appreciated and critical communications between T cells and host Ag-presenting cells (APC), which cross-present tumor Ag, it is likely that dendritic cell–based vaccine maneuvers that promote sensitization of T1-committed L-selectinlow antitumimportant role in adoptive therapy strategies.


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