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Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors

Nature Medicine volume 12, pages 335–341 (2006)Cite this article

Abstract

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 α 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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Figure 1: Tolerant CD8+ T cells do not proliferate in response to antigen but show in vivo cytolytic activity independent of FasL.
Figure 2: Tolerant and memory CD8+ T cells express IL-15 receptor and proliferate in response to IL-15.
Figure 3: IL-15 restores antigen responsiveness of tolerant CD8+ T cells.
Figure 4: IL-15 restores the ability of tolerant CD8+ T cells to respond to and effectively treat established tumor.

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Acknowledgements

This work was supported in part by grants CA33084 and CA18029 from the US National Institutes of Health/National Cancer Institute, and by a grant from the Leukemia and Lymphoma Society. R. Teague was supported by a Ruth L. Kirschstein National Research Service Award.

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Authors and Affiliations

  1. Department of Immunology, University of Washington School of Medicine, Office H-564 HSC, Box 357650, Seattle, 98195, Washington, USA

    Ryan M Teague, Blythe D Sather, Jilian A Sacks, Maria Z Huang, Michelle L Dossett, Junko Morimoto, Xiaoxio Tan, Claes Öhlén & Philip D Greenberg

  2. Fred Hutchinson Cancer Research Center, Program in Immunology, P.O. Box 19024, Seattle, 98109, Washington, USA

    Ryan M Teague, Michelle L Dossett, Junko Morimoto, Xiaoxio Tan, Claes Öhlén & Philip D Greenberg

  3. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, 92121, California, USA

    Susan E Sutton & Michael P Cooke

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Teague, R., Sather, B., Sacks, J. et al. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med 12, 335–341 (2006). https://doi.org/10.1038/nm1359

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