This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bendle, G. M. Articles by Stauss, H. J. Search for Related Content PubMed PubMed Citation Articles by Bendle, G. M. Articles by Stauss, H. J.

Induction of Unresponsiveness Limits Tumor Protection by Adoptively Transferred MDM2-Specific Cytotoxic T Lymphocytes

¹ Department of Immunology and ² Transplantation Biology Group of the MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom

There is evidence showing that high avidity CTLs can be more effective than low avidity CTLs for adoptive tumor immunotherapy. Because many T cell–recognized tumor antigens are nonmutated self-proteins, tolerance mechanisms are likely to render high avidity T cells unresponsive or cause T cell elimination by clonal deletion. We recently used the allo-restricted strategy to circumvent immunologic tolerance to a ubiquitously expressed tumor-associated protein, MDM2, and raised high avidity CTLs in humans and in mice. In this study, we investigated whether high avidity MDM2-specific CTLs can mediate tumor protection without causing damage to normal tissues in mice. Although the CTLs prolonged survival of tumor-bearing mice without causing damage to normal tissues, tumor protection was incomplete. We show that tumor growth occurred despite the continued presence of MDM2-specific CTLs and the continued susceptibility of tumor cells to CTL killing. However, analysis of the CTLs revealed that they had been rendered unresponsive in vivo because they did not produce interferon in response to antigen-specific stimulation. These experiments suggest that induction of unresponsiveness may be an important mechanism limiting the efficacy of adoptive CTL therapy.

This article has been cited by other articles:

				J. W. King, S. Thomas, F. Corsi, L. Gao, R. Dina, R. Gillmore, K. Pigott, A. Kaisary, H. J. Stauss, and J. Waxman IL15 Can Reverse the Unresponsiveness of Wilms' Tumor Antigen-Specific CTL in Patients with Prostate Cancer Clin. Cancer Res., February 15, 2009; 15(4): 1145 - 1154. [Abstract] [Full Text] [PDF]

				A. B. Frey and N. Monu Effector-phase tolerance: another mechanism of how cancer escapes antitumor immune response J. Leukoc. Biol., April 1, 2006; 79(4): 652 - 662. [Abstract] [Full Text] [PDF]

				S.-A. Xue, L. Gao, D. Hart, R. Gillmore, W. Qasim, A. Thrasher, J. Apperley, B. Engels, W. Uckert, E. Morris, et al. Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene-transduced human T cells Blood, November 1, 2005; 106(9): 3062 - 3067. [Abstract] [Full Text] [PDF]

				C. Mayr, D. M. Kofler, H. Buning, D. Bund, M. Hallek, and C.-M. Wendtner Transduction of CLL cells by CD40 ligand enhances an antigen-specific immune recognition by autologous T cells Blood, November 1, 2005; 106(9): 3223 - 3226. [Abstract] [Full Text] [PDF]

				E. C. Morris, A. Tsallios, G. M. Bendle, S.-a. Xue, and H. J. Stauss A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection PNAS, May 31, 2005; 102(22): 7934 - 7939. [Abstract] [Full Text] [PDF]