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Updated: Jun 28, 2025

Stimulation of Notch Signaling in Mouse Osteoclast Precursors
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Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of

Jay K Mandula1, Rosa A Sierra-Mondragon1, Rachel V Jimenez1

  • 1Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.

Immunity
|April 18, 2024
PubMed

Insights

Targeting Jagged2 (JAG2) in non-small cell lung cancer (NSCLC) enhances anti-tumor immunity. Blocking JAG2 activates macrophages and T cells, inhibiting tumor growth and improving survival in NSCLC models.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Notch signaling is crucial for tumor cell development and growth.
  • Immune evasion is a hallmark of non-small cell lung cancer (NSCLC).
  • The role of Notch ligands in NSCLC immune evasion requires further elucidation.

Purpose of the Study:

  • To investigate the role of the Notch ligand Jagged2 (JAG2) in immune evasion within NSCLC.
  • To determine if targeting JAG2 can overcome immunosuppression and enhance anti-tumor immunity in NSCLC.

Main Methods:

  • Analysis of JAG2 expression in NSCLC patient data.
  • Utilizing pre-clinical NSCLC models with Jag2 gene deletion.
  • Investigating immune cell infiltration and function, including macrophages and T cells.
  • Examining molecular pathways involving Notch ligands (DLL1/4), transcription factors (IRF4), and Nr4a.

Main Results:

  • Higher JAG2 expression in NSCLC correlated with poorer survival.
  • Deletion of Jag2 in cancer cells reduced tumor growth and boosted anti-tumor T cell responses.
  • Jag2-deficient tumors showed increased immunostimulatory macrophages.
  • Jag2 ablation promoted DLL1/4 expression, leading to IRF4 induction in macrophages, which was essential for anti-tumor effects.
  • Antibody-mediated JAG2 targeting inhibited tumor growth and activated macrophage-mediated immunity.

Conclusions:

  • Jagged2 plays a critical role in orchestrating immunosuppressive mechanisms within NSCLC.
  • Targeting Jagged2 can disrupt these immunosuppressive systems.
  • Blocking Jag2 can incite macrophage-mediated anti-tumor immunity, offering a potential therapeutic strategy for NSCLC.
Keywords:
JaggedNotch ligandsimmunosuppression in cancerimmunosuppressive myelopoiesismacrophage reprogrammingtumor-associated macrophages

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