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Soypeptide lunasin in cytokine immunotherapy for lymphoma.

Chang HC, Lewis D, Tung CY, Han L, Henriquez SM, Voiles L, Lupov IP, Pelloso D, Sinn AL, Pollok KE, de Lumen BO, Li F, Blum JS, Srivastava S, Robertson MJ - Cancer Immunol. Immunother. (2013)

Bottom Line: Adding lunasin to IL-12- or IL-2-stimulated NK cells demonstrated synergistic effects in the induction of IFNG and GZMB involved in cytotoxicity.In addition, NK cells stimulated with lunasin plus cytokines displayed higher tumoricidal activity than those stimulated with cytokines alone using in vitro and in vivo tumor models.The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation on target gene loci.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, 723 West Michigan Street, SL310, Indianapolis, IN, 46202, USA, huchang@iupui.edu.

ABSTRACT
Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We have previously reported that post-transplant lymphoma patients have an acquired deficiency of signal transducer and activator of transcription 4, which results in defective IFNγ production during clinical immunotherapy. With the goal of further improving cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that synergistically works with cytokines on natural killer (NK) cells. Peripheral blood mononuclear cells of healthy donors and post-transplant lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Adding lunasin to IL-12- or IL-2-stimulated NK cells demonstrated synergistic effects in the induction of IFNG and GZMB involved in cytotoxicity. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFNγ production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines displayed higher tumoricidal activity than those stimulated with cytokines alone using in vitro and in vivo tumor models. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation on target gene loci. Lunasin represents a different class of immune modulating agent that may augment the therapeutic responses mediated by cytokine-based immunotherapy.

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Rescuing IFNγ production by NK cells from lymphoma patients post-transplant. PBMCs of normal controls and post-transplant lymphoma patients were stimulated with medium only (−), IL-12 (10 ng/ml) and IL-2 (100 U/ml), IL-12 and IL-2 plus lunasin (lu, 20 μM), or lunasin alone for 1 day. The production of IFNγ at single-cell levels was analyzed using intracellular cytokine staining as described in Fig. 1a, and a representative dot plot from one control and patient is shown in a. The percentage of IFNγ positive NK populations (CD3 negative and CD56 positive) are presented as mean ± SD averaged from 6 normal controls and 5 patients (1 patient at 6–12 month and 4 patients at 3–6 months post-transplant) (b). *P ≤ 0.05
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Fig3: Rescuing IFNγ production by NK cells from lymphoma patients post-transplant. PBMCs of normal controls and post-transplant lymphoma patients were stimulated with medium only (−), IL-12 (10 ng/ml) and IL-2 (100 U/ml), IL-12 and IL-2 plus lunasin (lu, 20 μM), or lunasin alone for 1 day. The production of IFNγ at single-cell levels was analyzed using intracellular cytokine staining as described in Fig. 1a, and a representative dot plot from one control and patient is shown in a. The percentage of IFNγ positive NK populations (CD3 negative and CD56 positive) are presented as mean ± SD averaged from 6 normal controls and 5 patients (1 patient at 6–12 month and 4 patients at 3–6 months post-transplant) (b). *P ≤ 0.05

Mentions: As reported previously, STAT4 deficiency was observed in lymphoma patients after PBSCT [21]. Stimulation of patient PBMCs with both IL-12 and IL-2 resulted in production of IFNγ by NK populations using intracellular staining (Fig. 3a), albeit at a much lower percentage as compared to cells from normal controls (Fig. 3b). However, adding lunasin to the stimulation further increased the percentage of patient NK cells that produced IFNγ, which was similar to the level from normal controls stimulated with both cytokines (P = 0.446) (Fig. 3b). Thus, incorporating lunasin into cytokine-based treatment may rescue the production of IFNγ by NK cells from heavily treated lymphoma patients with acquired STAT4 deficiency.Fig. 3


Soypeptide lunasin in cytokine immunotherapy for lymphoma.

Chang HC, Lewis D, Tung CY, Han L, Henriquez SM, Voiles L, Lupov IP, Pelloso D, Sinn AL, Pollok KE, de Lumen BO, Li F, Blum JS, Srivastava S, Robertson MJ - Cancer Immunol. Immunother. (2013)

Rescuing IFNγ production by NK cells from lymphoma patients post-transplant. PBMCs of normal controls and post-transplant lymphoma patients were stimulated with medium only (−), IL-12 (10 ng/ml) and IL-2 (100 U/ml), IL-12 and IL-2 plus lunasin (lu, 20 μM), or lunasin alone for 1 day. The production of IFNγ at single-cell levels was analyzed using intracellular cytokine staining as described in Fig. 1a, and a representative dot plot from one control and patient is shown in a. The percentage of IFNγ positive NK populations (CD3 negative and CD56 positive) are presented as mean ± SD averaged from 6 normal controls and 5 patients (1 patient at 6–12 month and 4 patients at 3–6 months post-transplant) (b). *P ≤ 0.05
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3928510&req=5

Fig3: Rescuing IFNγ production by NK cells from lymphoma patients post-transplant. PBMCs of normal controls and post-transplant lymphoma patients were stimulated with medium only (−), IL-12 (10 ng/ml) and IL-2 (100 U/ml), IL-12 and IL-2 plus lunasin (lu, 20 μM), or lunasin alone for 1 day. The production of IFNγ at single-cell levels was analyzed using intracellular cytokine staining as described in Fig. 1a, and a representative dot plot from one control and patient is shown in a. The percentage of IFNγ positive NK populations (CD3 negative and CD56 positive) are presented as mean ± SD averaged from 6 normal controls and 5 patients (1 patient at 6–12 month and 4 patients at 3–6 months post-transplant) (b). *P ≤ 0.05
Mentions: As reported previously, STAT4 deficiency was observed in lymphoma patients after PBSCT [21]. Stimulation of patient PBMCs with both IL-12 and IL-2 resulted in production of IFNγ by NK populations using intracellular staining (Fig. 3a), albeit at a much lower percentage as compared to cells from normal controls (Fig. 3b). However, adding lunasin to the stimulation further increased the percentage of patient NK cells that produced IFNγ, which was similar to the level from normal controls stimulated with both cytokines (P = 0.446) (Fig. 3b). Thus, incorporating lunasin into cytokine-based treatment may rescue the production of IFNγ by NK cells from heavily treated lymphoma patients with acquired STAT4 deficiency.Fig. 3

Bottom Line: Adding lunasin to IL-12- or IL-2-stimulated NK cells demonstrated synergistic effects in the induction of IFNG and GZMB involved in cytotoxicity.In addition, NK cells stimulated with lunasin plus cytokines displayed higher tumoricidal activity than those stimulated with cytokines alone using in vitro and in vivo tumor models.The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation on target gene loci.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, 723 West Michigan Street, SL310, Indianapolis, IN, 46202, USA, huchang@iupui.edu.

ABSTRACT
Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We have previously reported that post-transplant lymphoma patients have an acquired deficiency of signal transducer and activator of transcription 4, which results in defective IFNγ production during clinical immunotherapy. With the goal of further improving cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that synergistically works with cytokines on natural killer (NK) cells. Peripheral blood mononuclear cells of healthy donors and post-transplant lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Adding lunasin to IL-12- or IL-2-stimulated NK cells demonstrated synergistic effects in the induction of IFNG and GZMB involved in cytotoxicity. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFNγ production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines displayed higher tumoricidal activity than those stimulated with cytokines alone using in vitro and in vivo tumor models. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation on target gene loci. Lunasin represents a different class of immune modulating agent that may augment the therapeutic responses mediated by cytokine-based immunotherapy.

Show MeSH
Related in: MedlinePlus