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

Autor:	Mandula JK; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Sierra-Mondragon RA; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Jimenez RV; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Chang D; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Mohamed E; California Northstate University, Elk Grove, CA 95757, USA., Chang S; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Vazquez-Martinez JA; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Cao Y; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Anadon CM; Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27708, USA., Lee SB; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Das S; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Rocha-Munguba L; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Pham VM; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Li R; Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Tarhini AA; 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., Furqan M; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA., Dalton W; Aster Insights, Tampa, FL 34667, USA., Churchman M; Aster Insights, Tampa, FL 34667, USA., Moran-Segura CM; Advanced Analytical and Digital Laboratory, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Nguyen J; Advanced Analytical and Digital Laboratory, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Perez B; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Kojetin DJ; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Obermayer A; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Yu X; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Chen A; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA., Shaw TI; 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., Conejo-Garcia JR; Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27708, USA., Rodriguez PC; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. Electronic address: paulo.rodriguez@moffitt.org.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2024 May 14; Vol. 57 (5), pp. 1124-1140.e9. Date of Electronic Publication: 2024 Apr 17.
DOI:	10.1016/j.immuni.2024.03.020
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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