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Related Concept Videos

Cells of the Innate Immune Response01:28

Cells of the Innate Immune Response

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The innate immune response is an immediate and non-specific response against pathogens, acting swiftly to prevent the spread of infections. The primary cells involved in this response are phagocytes and natural killer (NK) cells.
Phagocytes
Phagocytes police the peripheral tissues by removing cellular debris and responding to the invasion of foreign substances or pathogens. Many phagocytes attack and remove microorganisms even before lymphocytes detect them. The human body has two general...
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Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
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FcɛR1γ-based activating chimeric antigen receptor enhanced natural killer cell function against HLA-E+ cells.

Lewis L Lanier1,2, John R Greenland3,4, Frank Momburg5,6

  • 1Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, United States.

Journal of Immunology (Baltimore, Md. : 1950)
|November 2, 2025
PubMed
Summary

Engineered Fc receptor gamma (FcɛR1γ) enhances natural killer (NK) cell function against cancer, even when tumor cells express HLA-E. Modified NK cells show improved cancer cell killing, advancing NK cell-based immunotherapy.

Keywords:
FcɛR1γHLA-Eactivating receptorschimeric antigen receptornatural killer cells

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Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
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Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies

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Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Therapy

Background:

  • Fc receptor gamma (FcɛR1γ) is a transmembrane adaptor protein crucial for activating receptors in human natural killer (NK) cells.
  • Cancer cells expressing HLA-E can suppress NK cell activity via NKG2A interaction, hindering anti-tumor immune responses.
  • Enhancing NK cell effector functions is a key goal in developing novel cancer immunotherapies.

Purpose of the Study:

  • To engineer human NK cells with a modified FcɛR1γ incorporating a 4-1BB co-stimulatory motif to enhance their anti-cancer activity.
  • To evaluate the efficacy of chimeric antigen receptor (CAR) NK cells engineered with the modified FcɛR1γ against tumor cells, including those expressing HLA-E.

Main Methods:

  • Human NK cells were engineered to express a modified FcɛR1γ (FcɛR1γ41BB) containing a 4-1BB co-stimulatory domain.
  • A novel CAR construct (FCRG10) was generated, incorporating the modified FcɛR1γ41BB.
  • NK cell expression of activating receptors (NKp30, NKp46, CD16) and cytotoxic activity against target cells, including those expressing HLA-E, were assessed.

Main Results:

  • FcɛR1γ41BB expression upregulated NKp30, NKp46, and CD16, enhancing NK cell-mediated lysis of target cells.
  • FcɛR1γ41BB improved NK cell lytic function against HLA-E expressing cells compared to unmodified FcɛR1γ.
  • CAR NK cells expressing FCRG10 demonstrated superior cytotoxicity against tumor cells co-expressing B7H6, CD19, and HLA-E compared to conventional CAR NK cells.

Conclusions:

  • Modification of FcɛR1γ with a 4-1BB co-stimulatory motif significantly enhances NK cell lytic function via multiple activating receptors.
  • Engineered CAR NK cells (FCRG10) show improved efficacy in overcoming HLA-E-mediated NK cell suppression.
  • This approach holds promise for developing advanced NK cell-based cancer immunotherapies that co-recognize tumor antigens and stress ligands.