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

Ryan M. Teague, Blythe D. Sather, Jilian A. Sacks, Maria Z. Huang, Michelle L. Dossett, Junko Morimoto, Xiaoxio Tan, Susan E. Sutton, Michael P. Cooke, Claes Öhlén, Philip D. Greenberg

Research output: Contribution to journalArticlepeer-review

191 Scopus citations

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 cancer. 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 antigen. 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.

Original languageEnglish (US)
Pages (from-to)335-341
Number of pages7
JournalNature Medicine
Volume12
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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