IL-15 in the life and death of lymphocytes: Implications for cancer therapy and vaccine design

SY08-02 Interleukin-2 and Interleukin-15 have pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common, these two cytokines have contrasting roles in adaptive immune responses. The unique role of IL-2 is the elimination of self-reactive T cells and the maintenance of T regs to prevent autoimmunity. In contrast IL-15 is dedicated to the prolonged maintenance of memory CD8 T-cell responses to invading pathogens. In light of these functional differences, IL-15 may be superior to IL-2 in the immunotherapy of cancer and as a component of molecular vaccines where activated NK cells and a prolonged CD8 immune response are desirable. The Biology of IL-2 and IL-15: Implications for Cancer Therapy The immune system is dedicated toward a series of goals including: the generation of rapid innate and adaptive immune responses to invading pathogens; the elimination of autoreactive T-cells to generate tolerance to self and the maintenance of a specific memory response to pathogens. Such immune responses are regulated by a series of cytokines that include IL-2 and IL-15. IL-2 and IL-15 act through heterotrimeric receptors (1-3). IL-2 and IL-15 share the IL-2/IL-15R beta (CD122) and the common gamma receptor subunits (γc). Their high-affinity receptors also include the private alpha subunits IL-2R alpha and IL-15R alpha. Because IL-2 and IL-15 share the beta (CD122) and gamma (CD132) subunits, they also share a number of functions. However in many adaptive immune responses IL-2 and IL-15 have distinct and often competing roles (2, 3). IL-2 through its unique role in activation-induced cell death (AICD) and its action in the maintenance and fitness of CD4+ CD25+ regulatory T-cells (T reg cells) is involved in the elimination of self-reactive T-cells that play a role in the pathogenesis of immune disorders (4). By contrast IL-15 is important for the maintenance of long-lasting, high-avidity T-cell responses to invading pathogens by supporting the survival of CD8+ memory T cells. After the distinct roles of IL-2 and IL-15 had been defined an important question emerged. How can these two cytokines have distinct functions given that they bind receptors with two subunits in common and that they both initiate a signaling pathway involving JAK1, JAK3 and STAT5? One critical factor involves the distinct modes of action of IL-2 and IL-15. IL-2 is a secreted molecule that binds to preformed high-affinity heterotrimeric receptors at the surface of activated cells. In contrast, IL-15 is only secreted in small quantities and is mainly membrane bound. It induces signaling in the context of cell-cell context. In the case of IL-15 stimulation of monocytes or DCs with interferon together with activation of NF-kappa B induces the coordinate expression of IL-15 and IL-15R alpha. IL-15R alpha presents IL-15 intrans to cells that express IL-2/IL-15R beta and γc but not IL-15R alpha (5). Such IL-2/IL-15R beta and γc expressing targets of IL-15/IL-15R alpha system include CD8+ memory T-cells and NK cells. Implications of Distinct IL-2 and IL-15 Actions in their Use in the Therapy of Cancer: IL-2 has been approved for use in patients with metastatic renal cell carcinoma and malignant melanoma. However IL-2 is not optimal for this action. In the presence of IL-2 the cytotoxic lymphocytes may interpret the tumors as self and may die by AICD or the immune response made be inhibited by IL-2 dependent CD4+ CD25+ T reg cells. By contrast IL-15 with its activation of T cells and NK cells, its inhibitory action on AICD and its role in the persistence of CD8+ memory T-cells may be superior to IL-2 in the treatment of cancer and as a component of vaccines. IL-15 has proven of value in murine syngeneic tumor model systems in the prevention and treatment of neoplasia (6). On the basis of these studies, in conjunction with the Biopharmaceutical Development Program (BDP), National Cancer Institute at NIH, we have begun to produce recombinant IL-15 under good manufacturing practice conditions for use instead of IL-2 in human clinical trials involving patients with metastatic renal cell cancer or malignant melanoma. In parallel efforts that were designed to take advantage of the role of IL-15 in the generation and maintenance of memory T-cells, the gene encoding IL-15 was incorporated into molecular vaccines (7). When administered to mice vaccinia vectors co-expressing IL-15 and an HIV antigen but not those expressing IL-2 induced long-lasting cellular immunity to this antigen. Such molecular vaccines incorporating IL-15 may provide a new perspective for preventive vaccines against HIV and other infectious agents including human papillomavirus (HPV) that are associated with malignancy. Disorders of IL-15/IL-15R System: IL-15 is a dangerous proinflammatory cytokine that may be at the apex of an inflammatory cytokine cascade where it proceeds TNF alpha and the downstream cytokines, IL-1, IL-6 as well as proinflammatory cytokines (8). Furthermore, IL-15 may contribute to autoimmune disorders by inhibiting self tolerance mediated by IL-2 induced AICD and by facilitating the maintenance of CD8+ memory T-cell survival including that of self-directed memory cells. Indeed, disregulated IL-15 expression has been reported in patients with an array of autoimmune and inflammatory diseases including rheumatoid arthritis, refractory celiac syndrome and associated CD8 lymphoma as well as diseases associated with the retrovirus HTLV-I (13). Several agents that inhibit IL-15 activity have been developed including mutant IL-15 molecules and antibodies specific for IL-15 or IL-2/IL-15R beta. Our own approach involves a humanized antibody (Hu-MiK-Beta-1) specific for IL-2/IL-15R beta (CD122) that blocks the transpresentation of IL-15 from antigen-presenting cells to target NK and CD8 T-cells (3). In an effort to test the hypothesis that IL-15 plays a role in the pathogenesis of select autoimmune diseases including those associated with neoplasia, clinical trials have been initiated with humanized Mik-Beta-1 in patients with HTLV-I associated disorders, T-cell large granular lymphocytic leukemia as well as refractory celiac disease with emerging CD8 lymphoma. Conclusions: Our emerging understanding of the IL-2/IL-2R and IL-15/IL-15R systems is providing the scientific basis for the development of rational approaches that use IL-15 for the therapy of malignancy and autoimmunity as well as a component of molecular vaccines against infectious diseases and malignancy. Furthermore, given the role of IL-15 in the maintenance of CD8 memory T-cells as well as the expression of proinflammatory cytokines involved in the pathogenesis of autoimmune diseases, to inhibit the actions of IL-15, therapeutic strategies have been initiated that might prove to be of value in the treatment of such T-cell mediated autoimmune inflammatory diseases. References: 1. Waldmann,T.A. and Tagaya,Y. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens, Annu Rev Immunol, 17: 19-49, 1999. 2. Waldmann,T.A., Dubois,S. and Tagaya,Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy, Immunity, 14: 105-110, 2001. 3. Waldmann,T.A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design, Nat Rev Immunol, 6: 595-601, 2006. 4. Lenardo,M.J. Fas and the art of lymphocyte maintenance, J.Exp.Med., 183: 721-724, 1996. 5. Dubois,S., Mariner,J., Waldmann,T.A. and Tagaya,Y. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells, Immunity, 17: 537-547, 2002. 6. Kobayashi,H., Dubois,S., Sato,N., Sabzevari,H., Sakai,Y., Waldmann,T.A. and Tagaya,Y. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance, Blood, 105: 721-727, 2005. 7. Oh,S., Berzofsky,J.A., Burke,D.S., Waldmann,T.A. and Perera,L.P. Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity, Proc Natl Acad Sci U S A, 100: 3392-3397, 2003. 8. McInnes,I.B., Leung,B.P., Sturrock,R.D., Field,M. and Liew,F.Y. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis, Nat.Med., 3: 189-195, 1997. #