2. Academic Validation
  3. Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages

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

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: paulo.rodriguez@moffitt.org.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15860
    99.90%, Notch Inhibitor