Interleukin-15/Interleukin-15RA Complexes Promote Destruction of Established Tumors by Reviving Tumor-Resident CD8 + T Cells Mathieu Epardaud, 1,5 Kutlu G. Elpek, 1 Mark P. Rubinstein, 6 Ai-ris Yonekura, 1,2 Angelique Bellemare-Pelletier, 1 Roderick Bronson, 3 Jessica A. Hamerman, 7 Ananda W. Goldrath, 6 and Shannon J. Turley 1,4 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 Abstract Tumors often escape immune-mediated destruction by sup- pressing 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-15RA. Here, we report that in vivo delivery of IL-15/IL-15RA complexes triggers rapid and significant regression of estab- lished solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15RB + cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15RA 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-15RA 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] Introduction Cancer immunosurveillance is the process whereby innate and adaptive immune mechanisms suppress the growth of tumors (1, 2). CD8 + T cells and natural killer (NK) cells play important roles in this process by directly killing malignant cells (1, 3–5). Cancer immunosurveillance is regulated not only by the immune system but also by elements of the tumor microenvironment, including malignant cells, tumor stroma, and the vasculature (6). Indeed, tumors can escape immunosurveillance by disabling the function of cytolytic lymphocytes and antigen-presenting cells, by prevent- ing blood-borne lymphocytes from infiltrating malignant tissue or by inducing tolerance (1, 7, 8). Various immunotherapeutic strategies have been developed for the treatment of human cancers. Cancer vaccines strive to incite robust antitumor immunity by immunizing the cancer patient with different forms of tumor antigens; however, their effect on tumor burden has been modest (9–11). In adoptive cell therapy (ACT), patients are infused with autologous, tumor-specific T cells that can be derived from tumor-infiltrating lymphocytes (TIL) or from peripheral blood lymphocytes engineered to express a tumor- specific T-cell receptor (12, 13). Although ACT has been successful in inducing objective responses in select cancers such as metastatic melanoma, most patients still fail to respond despite increased frequencies of circulating, tumor-specific lymphocytes (14, 15). It is becoming increasingly clear that clinical efficacy in cancer immunotherapy may be more dependent on the ability of immune effector cells to access the tumor and to exert their tumoricidal functions therein rather than on the numbers of circulating, tumor- specific lymphocytes (16–19). Unfortunately, fewer efforts have focused on designing therapies that target tumor-resident T cells and boost their effector function in situ . Thus, new approaches are needed that either facilitate the infiltration of circulating leukocytes into solid tumors or that effectuate the tumoricidal function of TILs that persist in a functionally suppressed state in the malignant lesion. The administration of cytokines to augment immunosurveillance has proven efficacious in the treatment of select cancers (20). For example, IL-2 is Food and Drug Administration approved for the treatment of renal cell carcinoma and metastatic melanoma. However, IL-2 therapy is limited by systemic toxicity, poor biological activity, and an inability to induce antitumor activity in most cancer patients (21) due to selective promotion of T-cell activation–induced cell death (AICD) and expansion of T regulatory cells (Treg; refs. 22–26). Highly related to IL-2 is the cytokine IL-15 (27, 28), which lacks these adverse effects. In addition to sharing the use of two receptor subunits (IL-2Rh/ CD122 and IL-2Rg/CD132) and inducing similar intracellular signaling events, both IL-15 and IL-2 induce the mild expansion of memory CD8 + T cells, NK cells, and NKT cells (22). IL-15 has shown antitumor efficacy and enhances the effects of chemother- apy and ACT (29–32). However, like IL-2, IL-15 has a short half-life and high doses are needed to achieve biological responses in vivo (33, 34). Recently, it was shown that the biological activity of IL-15 could be increased f50-fold by administering preformed com- plexes of IL-15 and its soluble receptor, IL-15Ra (35, 36). This increase in activity is likely due to an increased half-life of the complex compared with IL-15 alone and that IL-15 is being presented by IL-15Ra to CD122 + cells similarly to how it is thought to be presented by dendritic cells in vivo . Compared with IL-15, IL-15/IL-15Ra complexes induce a dramatic expansion of CD122 hi cells, including antigen-experienced CD44 hi CD8 + memory and Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). M. Epardaud and K.G. Elpek contributed equally to this work. 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@dfci.harvard.edu. I2008 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-08-0045 Cancer Res 2008; 68: (8). April 15, 2008 2972 www.aacrjournals.org Research Article Research. on February 6, 2016. © 2008 American Association for Cancer cancerres.aacrjournals.org Downloaded from