Publication de 6 numéros par an
ISSN Imprimer: 1040-8401
ISSN En ligne: 2162-6472
Indexed in
T-Cell Adoptive Therapy of Tumors: Mechanisms of Improved Therapeutic Performance
RÉSUMÉ
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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Chen Aoshuang, Liu Shanrong, Park David, Kang Youmin, Zheng Guoxing, Depleting Intratumoral CD4+CD25+ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer, Cancer Research, 67, 3, 2007. Crossref
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Wang Li-Xin, Chen Bing-Guan, Plautz Gregory E., Adoptive Immunotherapy of Advanced Tumors with CD62 L-Selectinlow Tumor-Sensitized T Lymphocytes Following Ex Vivo Hyperexpansion, The Journal of Immunology, 169, 6, 2002. Crossref
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Chakraborty Mala, Abrams Scott I., Camphausen Kevin, Liu Kebin, Scott Tamalee, Coleman C. Norman, Hodge James W., Irradiation of Tumor Cells Up-Regulates Fas and Enhances CTL Lytic Activity and CTL Adoptive Immunotherapy, The Journal of Immunology, 170, 12, 2003. Crossref
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Wang Li-Xin, Kjaergaard Jorgen, Cohen Peter A., Shu Suyu, Plautz Gregory E., Memory T Cells Originate from Adoptively Transferred Effectors and Reconstituting Host Cells after Sequential Lymphodepletion and Adoptive Immunotherapy, The Journal of Immunology, 172, 6, 2004. Crossref
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Caldwell Sheila A., Ryan Mary H., McDuffie Elwood, Abrams Scott I., The Fas/Fas Ligand Pathway Is Important for Optimal Tumor Regression in a Mouse Model of CTL Adoptive Immunotherapy of Experimental CMS4 Lung Metastases, The Journal of Immunology, 171, 5, 2003. Crossref