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Interleukin-15/Interleukin-15R Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8⁺ T Cells

¹ Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; ² Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology; ³ Harvard Medical School; ⁴ Department of Pathology, Harvard Medical School, Boston, Massachusetts; ⁵ Department of Virologie et Immunologie Moleculaires UR892, INRA, Domaine de Vilvert, Jouy-en-Josas, France; ⁶ Division of Biology, University of California at San Diego, La Jolla, California; and ⁷ Immunology Program, Benaroya Research Institute, Seattle, Washington

Requests for reprints: Shannon J. Turley, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, D1440a, Boston, MA 02115. Phone: 617-632-4990; Fax: 617-582-7999; E-mail: shannon_turley{at}dfci.harvard.edu.

Key Words: IL-15 complex • immunotherapy • tumor

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-15R. Here, we report that in vivo delivery of IL-15/IL-15R 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-15R 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-15R 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. [Cancer Res 2008;68(8):2972–83]