Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation

Mishra, Anjali; Liu, Shujun; Sams, Gregory H.; Curphey, Douglas P.; Santhanam, Ramasamy; Rush, Laura J.; Schaefer, Deanna M.W.; Falkenberg, Lauren G.; Sullivan, Laura A.; Jaroncyk, Laura; Xiao, Yang; Fisk, Harold A.; Wu, Lai-Chu; Hickey, Christopher; Chandler, Jason C.; Wu, Yue; Heerema, Nyla A.; Chan, Kenneth K.; Perrotti, Danilo; Zhang, Jianying; Porcu, Pierluigi; Racke, Frederick; Garzon, Ramiro; Lee, Robert J.; Marcucci, Guido; Caligiuri, Michael A.

doi:10.1016/j.ccr.2012.09.009

Cited by 150 publications

(161 citation statements)

References 47 publications

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“…However, IL-15 administration may also have untoward consequences. It has been implicated in the pathogenesis of acute lymphoblastic leukemia (35) and large granular lymphocyte leukemia (36). The administration of IL-15 also exacerbates graftversus-host disease after allogeneic bone marrow transplantation (17).…”

Section: Discussionmentioning

confidence: 99%

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

Guo

Luan

Rabacal

et al. 2015

The Journal of Immunology

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IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8+ T (mCD8+ T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8+ T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8+ T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA–induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA–mediated immunotoxicity.

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Section: Discussionmentioning

confidence: 99%

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

Guo

Luan

Rabacal

et al. 2015

The Journal of Immunology

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“…DCs serve as an important source for IL-15, which is presented to NK cells and enhances their cytolytic function (38,39). We identified a mechanism in human NK cells that allows the regulation of the powerful effect of IL-15 and that might exist to prevent autoimmunity (52). This mechanism seems to be dependent on IL-32a from DCs, as the latter is not induced beyond its basal levels in NK cells in response to IL-15 stimulation (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

Gorvel

Korenfeld

Tung

et al. 2017

The Journal of Immunology

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Cytokines produced by dendritic cells (DCs) can largely determine the direction of immunity. Transcriptional analysis revealed that besides IL-15, IL-32 was the only other cytokine expressed by human Langerhans cells. IL-32 is a human cytokine that exists in four main isoforms. Currently, little is known about the regulation and function of the various IL-32 isoforms. In this study, we found that IL-15 is a potent inducer of IL-32α in DCs. Because IL-15 promotes NK cell activation, we investigated the interplay between IL-32 and IL-15 and their role in NK cell activity. We show that IL-32α acts on NK cells to inhibit IL-15–mediated STAT5 phosphorylation and to suppress their IL-15–induced effector molecule expression and cytolytic capacity. IL-32α also acted on DCs by downregulating IL-15–induced IL-18 production, an important cytokine in NK cell activity. Blocking IL-32α during DC:NK cell coculture enhanced NK cell effector molecule expression as well as their cytolytic capacity. Taken together, our findings suggest a feedback inhibition of IL-15–mediated NK cell activity by IL-32α.

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“…Regulated provision of transgene IL-15 in this manner may also obviate, or at least reduce, potential adverse events associated with nonspecific overexpression of transgene IL-15 in vivo. [14][15][16][17] We observed that DCIL-15 was superior to rIL-15 in promoting both murine and human DC functionality and therapeutic cancer vaccine efficacy in multiple distinct and clinically-relevant murine tumor models ( 10 , Figs. 1-6 (Fig.…”

Section: -1248-52mentioning

confidence: 99%

“…[6][7][8][9][10][11][12] Unfortunately, high-doses of IL-15 (necessary for its bioactivity in vivo) via systemic administration of recombinant IL-15 protein (rIL-15) or overexpression of transgene IL-15 have untoward side-effects [e.g., stimulating tumor cell growth, activating negative regulators (e.g., programmed death-1) in CD8 C T cells, exacerbating xenogeneic graft-vs.-host-disease or autoimmunity, and functioning as an "oncogene" resulting in progressive CD8 C T or NK leukemia], [13][14][15][16][17] which have served to limit its benefit-to-risk ratio in the clinic, despite pre-clinical findings supporting the safety of rIL-15 in rhesus macaques. 18 IL-15 agonists (e.g., IL-15/IL15Ra-Fc complex and IL-15/IL-15Ra fusion protein) reduce the dose of delivered IL-15 required to reach biologicallymeaningful levels in vivo.…”

Section: Introductionmentioning

confidence: 99%

Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency

et al. 2014

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IL-15 supports improved antitumor immunity. How to best incorporate IL-15 into vaccine formulations for superior cancer immunotherapy remains a challenge. DC-derived IL-15 (DCIL-15) notably has the capacity to activate DC, to substitute for CD4 C Th and to potentiate vaccine efficacy making IL-15-based therapies attractive treatment options. We observed in transplantable melanoma, glioma and metastatic breast carcinoma models that DCIL-15-based DNA vaccines in which DC specifically express IL-15 and simultaneously produce tumor Aghsp70 were able to mediate potent therapeutic efficacy that required both host Batf3C DC and CD8 C T cells. In an inducible Braf V600E /Pten-driven murine melanoma model, DCIL-15 (not rIL-15)-based DNA vaccines elicited durable therapeutic CD8C T cell-dependent antitumor immunity. DCIL-15 was found to be superior to rIL-15 in "licensing" both mouse and human DC, and for activating CD8 C T cells. Such activation occurred even in the presence of Treg, without a need for CD4 C Th, but was IL-15/IL-15Ra-dependent. A single low-dose of DCIL-15 (not rIL-15)-based DC vaccines induced therapeutic antitumor immunity. CD14C DC emigrating from human skin explants genetically-immunized by IL-15 and Aghsp70 were more effective than similar DC emigrating from the explants genetically-immunized by Aghsp70 in the presence of rIL-15 in expressing membrane-bound IL-15/IL-15Ra and activating CD8 C T cells. These results support future clinical use of DCIL-15 as a therapeutic agent in battling cancer.

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Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation

Cited by 150 publications

References 47 publications

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

IL-15 Superagonist–Mediated Immunotoxicity: Role of NK Cells and IFN-γ

Dendritic Cell–Derived IL-32α: A Novel Inhibitory Cytokine of NK Cell Function

Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency

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