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

Ryan M Teague ¹, Blythe D Sather , Jilian A Sacks , Maria Z Huang , Michelle L Dossett , Junko Morimoto , Xiaoxio Tan , Susan E Sutton , Michael P Cooke , Claes Ohlén , Philip D Greenberg

Affiliations

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

PMID: 16474399
98 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 alpha 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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