Nature Medicine
- 12, 335 - 341 (2006)
Published online: 12 February 2006; | doi:10.1038/nm1359
Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumorsRyan M Teague1, 2, Blythe D Sather1, Jilian A Sacks1, Maria Z Huang1, Michelle L Dossett1, 2, Junko Morimoto1, 2, Xiaoxio Tan1, 2, Susan E Sutton3, Michael P Cooke3, Claes Öhlén1, 2 & Philip D Greenberg1, 21
Department of Immunology, University of Washington School of Medicine, Office H-564 HSC, Box 357650, Seattle, Washington 98195, USA. 2
Fred Hutchinson Cancer Research Center, Program in Immunology, P.O. Box 19024, Seattle, Washington 98109, USA. 3
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
Correspondence should be addressed to Philip D Greenberg pgreen@u.washington.edu CD8+ T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer1,
2,
3. Generating effective CD8+ T cell–mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8+ T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen4. Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor  chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8+ T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.
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