Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo.
IL-15 has substantial potential as an immunotherapeutic agent for augmenting immune responses. However, the activity of IL-15 is mediated by a unique mechanism in which the cytokine is transpresented by cell-bound high-affinity IL-15Ralpha to target cells expressing the IL-15Rbeta and the common gamma-chain. Thus, the efficacy of administered IL-15 alone may be limited by the availability of free IL-15Ralpha. We now show that administration of soluble IL-15/IL-15Ralpha complexes greatly enhanced IL-15 half-life and bioavailability in vivo. Treatment of mice with this complex, but not with IL-15 alone, resulted in robust proliferation of memory CD8 T cells, NK cells, and NK T cells. The activity of the complex required IL-15Rbeta, but not IL-15Ralpha, expression by the responding cells and was IL-7-independent. Interestingly, IL-15/IL-15Ralpha immunotherapy also caused naive CD8 T cell activation and development into effector cells and long-term memory T cells. Lastly, complexed IL-15, as compared with IL-15 alone, dramatically reduced tumor burden in a model of B16 melanoma. These findings hold significant importance for the use of IL-15 as a potential adjuvant/therapeutic and inducer of homeostatic proliferation, without the necessity for prior immunodepletion.
Stoklasek
Thomas A
TA
Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
Schluns
Kimberly S
KS
Lefrançois
Leo
L
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation; D004359:Drug Therapy, Combination; D006207:Half-Life; D007156:Immunologic Memory; D007167:Immunotherapy; D019409:Interleukin-15 / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053647:Receptors, Interleukin-15 / Q000627:therapeutic use
C508025:Il15ra protein, mouse; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D015851:Interleukin-7; D053647:Receptors, Interleukin-15