Interleukin-15/interleukin-15Rα complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells

Mathieu Epardaud, Kutlu G. Elpek, Mark P. Rubinstein, Ai Ris Yonekura, Angelique Bellemare-Pelletier, Roderick Bronson, Jessica A. Hamerman, Ananda W. Goldrath, Shannon J. Turley

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

Tumors often escape immune-mediated destruction by suppressing lymphocyte infiltration or effector function. New approaches are needed that overcome this suppression and thereby augment the tumoricidal capacity of tumor-reactive lymphocytes. The cytokine interleukin-15 (IL-15) promotes proliferation and effector capacity of CD8+ T cells, natural killer (NK) cells, and NKT cells; however, it has a short half-life and high doses are needed to achieve functional responses in vivo. The biological activity of IL-15 can be dramatically increased by complexing this cytokine to its soluble receptor, IL-15Rα. Here, we report that in vivo delivery of IL-15/IL-15Rα complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL- 15Rβ+ cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15Rα complexes, the destruction of solid tumors was orchestrated by tumor-resident rather than newly infiltrating CD8 + T cells. Our data provide novel insights into the use of IL-15/IL-15Rα complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections.

Original languageEnglish
Pages (from-to)2972-2983
Number of pages12
JournalCancer Research
Volume68
Issue number8
DOIs
StatePublished - 15 Apr 2008
Externally publishedYes

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