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

Jay K Mandula; Rosa A Sierra-Mondragon; Rachel V Jimenez; Darwin Chang; Eslam Mohamed; Shiun Chang; Julio A Vazquez-Martinez; Yu Cao; Carmen M Anadon; Sae Bom Lee; Satyajit Das; Léo Rocha-Munguba; Vincent M Pham; Roger Li; Ahmad A Tarhini; Muhammad Furqan; William Dalton; Michelle Churchman; Carlos M Moran-Segura; Jonathan Nguyen; Bradford Perez; Douglas J Kojetin; Alyssa Obermayer; Xiaoqing Yu; Ann Chen; Timothy I Shaw; Jose R Conejo-Garcia; Paulo C Rodriguez

doi:10.1016/j.immuni.2024.03.020

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

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

Jay K Mandula, Rosa A Sierra-Mondragon, Rachel V Jimenez, Darwin Chang, Eslam Mohamed, Shiun Chang, Julio A Vazquez-Martinez, Yu Cao, Carmen M Anadon, Sae Bom Lee, …

Immunity (Cambridge, Mass.), Vol.57(5), pp.1124-1140.e9

05/14/2024

DOI: 10.1016/j.immuni.2024.03.020

PMCID: PMC11096038

PMID: 38636522

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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.

macrophage reprogramming

immunosuppression in cancer

Notch ligands

Jagged

immunosuppressive myelopoiesis

tumor-associated macrophages

Details

Title: Subtitle: Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages
Creators: Jay K Mandula - Moffitt Cancer Center
Rosa A Sierra-Mondragon - Moffitt Cancer Center
Rachel V Jimenez - Moffitt Cancer Center
Darwin Chang - Moffitt Cancer Center
Eslam Mohamed - California Northstate University
Shiun Chang - Moffitt Cancer Center
Julio A Vazquez-Martinez - Moffitt Cancer Center
Yu Cao - Moffitt Cancer Center
Carmen M Anadon - Duke University School of Medicine
Sae Bom Lee - Moffitt Cancer Center
Satyajit Das - Moffitt Cancer Center
Léo Rocha-Munguba - Moffitt Cancer Center
Vincent M Pham - Moffitt Cancer Center
Roger Li - Moffitt Cancer Center
Ahmad A Tarhini
Muhammad Furqan - University of Iowa
William Dalton - Aster Insights, Tampa, FL 34667, USA
Michelle Churchman
Carlos M Moran-Segura - Moffitt Cancer Center
Jonathan Nguyen - Moffitt Cancer Center
Bradford Perez - Moffitt Cancer Center
Douglas J Kojetin - Vanderbilt University School of Medicine
Alyssa Obermayer - Moffitt Cancer Center
Xiaoqing Yu - Moffitt Cancer Center
Ann Chen - Moffitt Cancer Center
Timothy I Shaw
Jose R Conejo-Garcia - Duke University School of Medicine
Paulo C Rodriguez - Moffitt Cancer Center
Resource Type: Journal article
Publication Details: Immunity (Cambridge, Mass.), Vol.57(5), pp.1124-1140.e9
DOI: 10.1016/j.immuni.2024.03.020
PMID: 38636522
PMCID: PMC11096038
NLM abbreviation: Immunity
ISSN: 1074-7613
eISSN: 1097-4180
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R01-CA262121, R01-CA233512, P01-CA250984, R01-CA27303
Language: English
Electronic publication date: 04/11/2024
Date published: 05/14/2024
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984586459002771

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