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Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.

ABSTRACT: Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2R? and the common ?-chain (?(c)). Here we found that in the structure of the IL-15-IL-15R?-IL-2R?-?(c) quaternary complex, IL-15 binds to IL-2R? and ?(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2R?-IL-2R?-?(c) complex, despite their different receptor-binding chemistries. IL-15R? substantially increased the affinity of IL-15 for IL-2R?, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2R?-?(c) dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2R? versus IL-15R? determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.

SUBMITTER: Ring AM

PROVIDER: S-EPMC3501574 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.

Ring Aaron M AM Lin Jian-Xin JX Feng Dan D Mitra Suman S Rickert Mathias M Bowman Gregory R GR Pande Vijay S VS Li Peng P Moraga Ignacio I Spolski Rosanne R Ozkan Engin E Leonard Warren J WJ Garcia K Christopher KC

Nature immunology 20121028 12

Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ(c)). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ(c) quaternary complex, IL-15 binds to IL-2Rβ and γ(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ(c) complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and thi ...[more]

PMID: 23104097

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Project description:BACKGROUND:Anti(?)-programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) monotherapy fails to provide durable clinical benefit for most patients with carcinoma. Recent studies suggested that strategies to reduce immunosuppressive cells, promote systemic T-cell responses and lymphocyte trafficking to the tumor microenvironment (TME) may improve efficacy. N-809 is a first-in-class bifunctional agent comprising the interleukin (IL)-15 superagonist N-803 fused to two ?PD-L1 domains. Thus, N-809 can potentially stimulate effector immune cells through IL-15 and block immunosuppressive PD-L1. Here, we examined the antitumor efficacy and immunomodulatory effects of N-809 versus N-803+?PD-L1 combination. METHODS:The ability of N-809 to block PD-L1 and induce IL-15-dependent immune effects was examined in vitro and in vivo. Antitumor efficacy of N-809 or N-803+?PD-L1 was evaluated in two murine carcinoma models and an extensive analysis of immune correlates was performed in the tumor and tumor-draining lymph node (dLN). RESULTS:We demonstrate that N-809 blocks PD-L1 and induces IL-15-dependent immune effects. N-809 was well-tolerated and reduced 4T1 lung metastasis, decreased MC38 tumor burden and increased survival versus N-803+?PD-L1. Compared with N-803+?PD-L1, N-809 enhanced natural killer (NK) and CD8+ T-cell activation and function in the dLN and TME, relating to increased gene expression associated with interferon and cytokine signaling, lymphoid compartment, costimulation and cytotoxicity. The higher number of TME CD8+ T cells was attributed to enhanced infiltration, not in situ expansion. Increased TME NK and CD8+ T-cell numbers correlated with augmented chemokine ligands and receptors. Moreover, in contrast to N-803+?PD-L1, N-809 reduced immunosuppressive regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (M-MDSC) and M2-like macrophages in the TME. CONCLUSIONS:Our results suggest that N-809 functions by a novel immune mechanism to promote antitumor efficacy. Foremost, N-809 enhances intratumoral lymphocyte numbers by increasing trafficking via altered chemokine levels in the TME and chemokine receptor expression on CD8+ T cells and NK cells. In addition, N-809 reduces immunosuppressive and pro-tumorigenic immune cells in the TME, including Treg, M2-like macrophages and M-MDSC. Overall, these novel effects of N-809 promote an inflamed TME, leading to lower tumor burden and increased survival. These results provide mechanistic insight and rationale supporting the potential clinical study of N-809 in patients with carcinoma.

Dataset Information

Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.

Publications

Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.

Similar Datasets

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