Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors.
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.
Department of Immunology, University of Washington School of Medicine, Office H-564 HSC, Box 357650, Seattle, Washington 98195, USA.
Ryan M
RM
Teague
Blythe D
BD
Sather
Jilian A
JA
Sacks
Maria Z
MZ
Huang
Michelle L
ML
Dossett
Junko
J
Morimoto
Xiaoxio
X
Tan
Susan E
SE
Sutton
Michael P
MP
Cooke
Claes
C
Ohlén
Philip D
PD
Greenberg
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D049109:Cell Proliferation; D053222:Fas Ligand Protein; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000628:therapy*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
D016827:CD8 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D008562:Membrane Glycoproteins; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D048069:Tumor Necrosis Factors