Evidence map›Paper›PMID 39053944›Full record

ArticleJournal for immunotherapy of cancer2024

Enhanced IL-15-mediated NK cell activation and proliferation by an ADAM17 function-blocking antibody involves CD16A, CD137, and accessory cells.

Anders W Matson, Rob Hullsiek, Kate J Dixon, Sam Wang, Anders J Lindstedt, Ryan R Friess, Shee Kwan Phung, Tanya S Freedman, Martin Felices, Emily N Truckenbrod and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal for immunotherapy of cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Anders W MatsonGraduate Program in Comparative and Molecular Biosciences, University of Minnesota, Saint Paul, Minnesota, USA.
Rob HullsiekGraduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, Minnesota, USA.
Kate J DixonDepartment of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
Sam WangDepartment of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
Anders J LindstedtGraduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, Minnesota, USA.ORCID http://orcid.org/0000-0003-1988-5163
Ryan R FriessGraduate Program in Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA.
Shee Kwan PhungGraduate Program in Comparative and Molecular Biosciences, University of Minnesota, Saint Paul, Minnesota, USA.
Tanya S FreedmanCenter for Immunology, University of Minnesota, Minneapolis, Minnesota, USA.ORCID http://orcid.org/0000-0001-5168-5829
Martin FelicesDepartment of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.ORCID http://orcid.org/0000-0002-5945-0634
Emily N TruckenbrodDepartment of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
Jianming WuDepartment of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
Jeffrey S MillerCenter for Immunology, University of Minnesota, Minneapolis, Minnesota, USA.
Bruce WalcheckDepartment of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, Minnesota, USA walch003@umn.edu.ORCID http://orcid.org/0000-0003-1933-3887

Funding

Trial Design and Biostatistical Support CoreP01CA065493 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI J SUNIL RAO · 1995 to 2026
$48.2M
Therapeutic Potential of Adaptive NK Cells in Cancer and TransplantationP01CA111412 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI FELICES, MARTIN · 2005 to 2025
$38.2M
TRAINING-PULMONARY CELL &MOLECULAR BIOLOGY &PHYSIOLOGYT32HL007741 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI DUDLEY, R. ADAMS, INGBAR, DAVID H · 1994 to 2023
$13.9M
Expression of recombinant Fc receptors by engineered NK cells to enhance cancer cell killingR01CA203348 · NCI · UNIVERSITY OF MINNESOTA · PI WALCHECK, BRUCE K, WU, JIANMING · 2016 to 2025
$4.4M
Targeting off-the-shelf iPSC-derived natural killer cells against solid tumorsR35CA283892 · NCI · UNIVERSITY OF MINNESOTA · PI Jeffrey S. Miller · 2023 to 2026
$3.7M
Medical Scientist Training ProgramT32GM156735 · NIGMS · UNIVERSITY OF MINNESOTA · PI YOJI SHIMIZU · 2025 to 2026
$2.6M
Roles of the Src-Family Kinases LynA and LynB in Macrophage Inflammatory SignalingR01AR073966 · NIAMS · UNIVERSITY OF MINNESOTA · PI FREEDMAN, TANYA S. · 2018 to 2022
$2.2M
NCI NIH HHS P01 CA065493NCI NIH HHS P01 CA111412NCI NIH HHS R01 CA203348NCI NIH HHS R35 CA283892NHLBI NIH HHS T32 HL007741NIAMS NIH HHS R01 AR073966NIGMS NIH HHS T32 GM156735
6 · The paper itself

Abstract

backgroundNatural killer (NK) cells are being extensively studied as a cell therapy for cancer. These cells are activated by recognition of ligands and antigens on tumor cells. Cytokine therapies, such as IL-15, are also broadly used to stimulate endogenous and adoptively transferred NK cells in patients with cancer. These stimuli activate the membrane protease ADAM17, which cleaves various cell-surface receptors on NK cells as a negative feedback loop to limit their cytolytic function. ADAM17 inhibition can enhance IL-15-mediated NK cell proliferation in vitro and in vivo. In this study, we investigated the underlying mechanism of this process.

methodsPeripheral blood mononuclear cells (PBMCs) or enriched NK cells from human peripheral blood, either unlabeled or labeled with a cell proliferation dye, were cultured for up to 7 days in the presence of rhIL-15±an ADAM17 function-blocking antibody. Different fully human versions of the antibody were generated; Medi-1 (IgG1), Medi-4 (IgG4), Medi-PGLALA, Medi-F(ab')

resultsThe ADAM17 function-blocking monoclonal antibody (mAb) Medi-1 markedly increased early NK cell activation by IL-15. By using different engineered versions of the antibody, we demonstrate involvement by CD16A, an activating Fcγ receptor and well-described ADAM17 substrate. Hence, Medi-1 when bound to ADAM17 on NK cells is engaged by CD16A and blocks its shedding, inducing and prolonging its signaling. This process did not promote evident NK cell fratricide or dysfunction. Synergistic signaling by Medi-1 and IL-15 enhanced the upregulation of CD137 on CD16A

conclusionsOur data reveal for the first time that CD16A and CD137 underpin Medi-1 enhancement of IL-15-driven NK cell activation and proliferation, respectively, with the latter requiring PBMC accessory cells. The use of Medi-1 represents a novel strategy to enhance IL-15-driven NK cell proliferation, and it may be of therapeutic importance by increasing the antitumor activity of NK cells in patients with cancer.

Indexed as

ADAM17 ProteinCell ProliferationInterleukin-15Killer Cells, NaturalLymphocyte ActivationReceptors, IgGGPI-Linked ProteinsHumansADAM17 ProteinADAM17 protein, humanFCGR3A protein, humanGPI-Linked ProteinsIL15 protein, humanInterleukin-15Receptors, IgGAntibodyCytokineImmune Checkpoint InhibitorImmune modulatoryInnate

Identifiers

PMID39053944
PMCPMC11284835

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.