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Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells.

ABSTRACT: The secondary analyses for correlates of risk of infection in the RV144 HIV-1 vaccine trial implicated vaccine-induced antibody-dependent cellular cytotoxicity (ADCC) responses in the observed protection, highlighting the importance of assessing such responses in ongoing and future HIV-1 vaccine trials. However, in vitro assays that detect ADCC activity in plasma from HIV-1 infected seropositive individuals are not always effective at detecting ADCC activity in plasma from HIV-1 vaccine recipients. In vivo, ADCC-mediating antibodies must operate at the site of infection, where effector cells are recruited and activated by a local milieu of chemokines and cytokines. Based on previous findings that interleukin 15 (IL-15) secretion increases during acute HIV-1 infection and enhances NK cell-mediated cytotoxicity, we hypothesized that IL-15 pretreatment of NK effector cells could be used to improve killing of infected cells by vaccine-induced antibodies capable of mediating ADCC. Using the HIV-1 infectious molecular clone (IMC)-infected target cell assay along with plasma samples from HIV-1 vaccine recipients, we found that IL-15 treatment of effector cells improved the ability of the vaccine-induced antibodies to recruit effector cells for ADCC. Through immunophenotyping experiments, we showed that this improved killing was likely due to IL-15 mediated activation of NK effector cells and higher intracellular levels of perforin and granzyme B in the IL-15 pretreated NK cells. We also found that using a 4-fold dilution series of plasma and subtraction of pre-vaccination responses resulted in lowest response rates among placebo recipients and significant separation between treatment groups. This represents the first attempt to utilize IL-15-treated effector cells and optimized analytical approaches to improve the detection of HIV-1 vaccine-induced ADCC responses and will inform analyses of future HIV vaccine clinical trials.

SUBMITTER: Fisher L

PROVIDER: S-EPMC6890556 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells.

Fisher Leigh L Zinter Melissa M Stanfield-Oakley Sherry S Carpp Lindsay N LN Edwards R Whitney RW Denny Thomas T Moodie Zoe Z Laher Fatima F Bekker Linda-Gail LG McElrath M Juliana MJ Gilbert Peter B PB Corey Lawrence L Tomaras Georgia G Pollara Justin J Ferrari Guido G

Frontiers in immunology 20191127

The secondary analyses for correlates of risk of infection in the RV144 HIV-1 vaccine trial implicated vaccine-induced antibody-dependent cellular cytotoxicity (ADCC) responses in the observed protection, highlighting the importance of assessing such responses in ongoing and future HIV-1 vaccine trials. However, <i>in vitro</i> assays that detect ADCC activity in plasma from HIV-1 infected seropositive individuals are not always effective at detecting ADCC activity in plasma from HIV-1 vaccine r ...[more]

PMID: 31827470

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Project description:Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in children. Despite intensive research in recent decades the prognosis for patients with metastatic or relapsed diseases has hardly improved. New therapeutic concepts in anti-tumor therapy aim to modulate the patient's immune system to increase its aggressiveness or targeted effects toward tumor cells. Besides surgery, radiotherapy and chemotherapy, immune activation by direct application of cytokines, antibodies or adoptive cell therapy are promising approaches. In the last years, adoptive transfer of natural killer (NK) cells came into the focus of translational medicine, because of their high cytotoxic potential against transformed malignant cells. A main challenge of NK cell therapy is that it requires a high amount of functional NK cells. Therefore, ex vivo NK cell expansion protocols are currently being developed. Many culturing strategies are based on the addition of feeder or accessory cells, which need to be removed prior to the clinical application of the final NK cell product. In this study, we addressed feeder cell-free expansion methods using common γ-chain cytokines, especially IL-15 and IL-21. Our results demonstrated high potential of IL-15 for NK cell expansion, while IL-21 triggered NK cell maturation and functionality. Hence, we established a two-phase expansion protocol with IL-15 to induce an early NK cell expansion, followed by short exposure to IL-21 that boosted the cytotoxic activity of NK cells against RMS cells. Further functional analyses revealed enhanced degranulation and secretion of pro-inflammatory cytokines such as interferon-γ and tumor necrosis factor-α. In a proof of concept in vivo study, we also observed a therapeutic effect of adoptively transferred IL-15 expanded and IL-21 boosted NK cells in combination with image guided high precision radiation therapy using a luciferase-transduced RMS xenograft model. In summary, this two-phased feeder cell-free ex vivo culturing protocol combined efficient expansion and high cytolytic functionality of NK cells for treatment of radiation-resistant RMS.

Dataset Information

Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells.

Publications

Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells.

Similar Datasets

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