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

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cancer Research (Impact Factor: 9.33). 05/2008; 68(8):2972-83. DOI: 10.1158/0008-5472.CAN-08-0045
Source: PubMed

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-15R alpha. Here, we report that in vivo delivery of IL-15/IL-15R alpha complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15R beta(+) cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15R alpha 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 alpha 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.

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    • "IL-15 presented in trans by pulmonary DCs is required to maintain effector cells in the lung following influenza infection, and either depletion of the DCs or blockade of IL-15 in the lung results in a dramatic increase in apoptosis of the antigen-specific CD8 T cells (McGill et al., 2010). Additionally, administration of IL-15-IL-15Ra complexes in tumor bearing mice revitalized the anti-tumor CTL responses, enhancing proliferation and cytotoxicity of the CTLs and reducing tumor burden (Epardaud et al., 2008; Stoklasek et al., 2006), further suggesting a role for IL-15 in sustaining specific CD8 T cell subsets in the tissues. A recently described distinct population of memory cells are sessile and reside in specific tissues, particularly barrier tissues such as the skin and intestinal mucosa (Casey et al., 2012; Jiang et al., 2012; Mackay et al., 2012; Wakim et al., 2010). "
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    ABSTRACT: Viral infections cause an immunological disequilibrium that provokes CD8 T cell responses. These cells play critical roles in purging acute infections, limiting persistent infections, and conferring life-long protective immunity. At every stage of the response anti-viral CD8 T cells are sensitive to signals from cytokines. Initially cytokines operate as immunological warning signs that inform of the presence of an infection, and also influence the developmental choices of the responding cells. Later during the course of the response other sets of cytokines support the survival and maintenance of the differentiated anti-viral CD8 T cells. Although many cytokines promote virus-specific CD8 T cells, other cytokines can suppress their activities and thus favor viral persistence. In this review we discuss how select cytokines act to regulate anti-viral CD8 T cells throughout the response and influence the outcome of viral infections.
    Virology 01/2013; 435(1):157-169. DOI:10.1016/j.virol.2012.09.012 · 3.32 Impact Factor
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    • "Importantly, it is upregulated on T cells by IFNα/β [3], and upon Ag encounter [4]–[5], during the first kinetics phase of brief contacts between T cells and antigen presenting cells, either in the presence or absence of adjuvant [6]. CD69 expression has been reported in infections [7]–[10], autoimmune diseases [11]–[16], and tumor infiltrates [17]–[18]. "
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    ABSTRACT: CD69 is rapidly upregulated on T cells upon activation. In this work we show that this is also the case for CD69 expression on dendritic cells (DC). Thus, the expression kinetics of CD69 on both cell types is reminiscent of the one of costimulatory molecules. Using mouse models of transgenic T cells, we aimed at evaluating the effect of monoclonal antibody (MAb)-based targeting and gene deficiency of CD69 expressed by either DC or T cells on the extent of antigen (Ag)-specific T cell priming, which could be the result of a putative role in costimulation as well as on DC maturation and Ag-processing and presentation. CD69 targeting or deficiency of DC did not affect their expression of costimulatory molecules nor their capacity to induce Ag-specific T cell proliferation in in vitro assays. Also, CD69 targeting or deficiency of transgenic T cells did not affect the minimal proliferative dose for different peptide agonists in vitro. In in vivo models of transgenic T cell transfer and local Ag injection, CD69 deficiency of transferred T cells did not affect the extent of the proliferative response in Ag-draining lymph nodes (LN). In agreement with these results, CD69 MAb targeting or gene deficiency of Vaccinia-virus (VACV) infected mice did not affect the endogenous formation of virus-specific CD8(+) T cell populations at the peak of the primary immune response. Altogether our results argue against a possible role in costimulation or an effect on Ag processing and presentation for CD69.
    PLoS ONE 10/2012; 7(10):e48593. DOI:10.1371/journal.pone.0048593 · 3.23 Impact Factor
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    • "Exploitation of the growth promoting activities of IL-15 supplementation is currently, after encouraging results in preclinical models [21]–[27], validated in clinical trials for tumor therapy and HIV vaccines. Nevertheless, our data showing that IL-15 can help Teff escape the suppression by Treg indicate it is advisable to monitor for autoimmune disease development when using IL-15. "
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    ABSTRACT: Due to its critical role in NK cell differentiation and CD8(+) T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+) T cells. The increased levels of IL-15 found in several CD4(+) T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4(+) T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+) and CD8(+) T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+) T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15Rα was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15Rβ, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4(+) T cell suppression by a gradually expanding CD25(High)CD4(+) T cell subset that expresses Foxp3 and originates from CD4(+)CD25(+) Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology.
    PLoS ONE 09/2012; 7(9):e45299. DOI:10.1371/journal.pone.0045299 · 3.23 Impact Factor
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