Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages

  • Immunity. 2024 May 14;57(5):1124-1140.e9. doi: 10.1016/j.immuni.2024.03.020.
Jay K Mandula  1 ,  Rosa A Sierra-Mondragon  1 ,  Rachel V Jimenez  1 ,  Darwin Chang  1 ,  Eslam Mohamed  2 ,  Shiun Chang  1 ,  Julio A Vazquez-Martinez  1 ,  Yu Cao  1 ,  Carmen M Anadon  3 ,  Sae Bom Lee  1 ,  Satyajit Das  1 ,  Léo Rocha-Munguba  1 ,  Vincent M Pham  1 ,  Roger Li  4 ,  Ahmad A Tarhini  5 ,  Muhammad Furqan  6 ,  William Dalton  7 ,  Michelle Churchman  7 ,  Carlos M Moran-Segura  8 ,  Jonathan Nguyen  8 ,  Bradford Perez  1 ,  Douglas J Kojetin  9 ,  Alyssa Obermayer  10 ,  Xiaoqing Yu  10 ,  Ann Chen  10 ,  Timothy I Shaw  11 ,  Jose R Conejo-Garcia  3 ,  Paulo C Rodriguez  12
Affiliations
  • 1. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 2. California Northstate University, Elk Grove, CA 95757, USA.
  • 3. Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27708, USA.
  • 4. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 5. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 6. Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA.
  • 7. Aster Insights, Tampa, FL 34667, USA.
  • 8. Advanced Analytical and Digital Laboratory, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 9. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 10. Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 11. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
  • 12. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. Electronic address: [email protected].
PMID: 38636522 DOI: 10.1016/j.immuni.2024.03.020
Abstract

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung Cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in Cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on Cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Keywords
Jagged; Notch ligands; immunosuppression in cancer; immunosuppressive myelopoiesis; macrophage reprogramming; tumor-associated macrophages.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15860
    FLI-06
    99.88%, Notch Inhibitor
    target: Notch
    Research Areas: Cancer