NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer
Background This study comprehensively investigates the association between the expression of nicotinamide N-methyltransferase (NNMT) and clinical outcomes of urothelial bladder cancer (UBC), as well as the molecular mechanisms by which NNMT in cancer-associated fibroblast (CAF) modulates tumor progr...
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BMJ Publishing Group
2024-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/7/e009281.full |
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| author | Jian Huang Bo Wang Dong Yan Tianxin Lin Lu Pei Hao Yu Wang He Kaiwen Li Meihua Yang Weibin Hou Honghui Zeng Xin-Ke Zhang Long Huang Haide Qin |
| author_facet | Jian Huang Bo Wang Dong Yan Tianxin Lin Lu Pei Hao Yu Wang He Kaiwen Li Meihua Yang Weibin Hou Honghui Zeng Xin-Ke Zhang Long Huang Haide Qin |
| author_sort | Jian Huang |
| collection | DOAJ |
| description | Background This study comprehensively investigates the association between the expression of nicotinamide N-methyltransferase (NNMT) and clinical outcomes of urothelial bladder cancer (UBC), as well as the molecular mechanisms by which NNMT in cancer-associated fibroblast (CAF) modulates tumor progression and immunotherapy resistance in UBC.Methods Single-cell transcriptomic analyses, immunohistochemical and immunofluorescence assays were performed on bladder cancer samples to validate the relationship between NNMT expression and clinical outcomes. A series of experiments, including chromatin immunoprecipitation assay, liquid chromatography tandem mass spectrometry assay, and CRISPR‒Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9) knockout, together with in vivo models, have been established to determine the molecular functions of NNMT in CAFs in UBC.Results We demonstrated that elevated expression of the nicotinamide adenine dinucleotide (NAD+) metabolism enzyme NNMT in CAFs (NNMT+ CAFs) was significantly associated with non-response to programmed death-ligand 1 (PD-L1) blockade immunotherapy in patients with UBC and predicted the unfavorable prognosis of UBC in two independent large cohorts. Targeting NNMT using the inhibitor 5-Amino-1-methylquinolinium iodide significantly reduced tumor growth and enhanced the apoptotic effects of the anti-PD-L1 antibody in UBC mouse models. Mechanistically, NNMT+ CAFs recruit tumor-associated macrophages via epigenetic reprogramming of serum amyloid A (SAA) to drive tumor cell proliferation and confer resistance to programmed death-1/PD-L1 blockade immunotherapy.Conclusions NNMT+ CAFs were significantly associated with non-response to PD-L1 blockade immunotherapy in patients with UBC. Elevated NNMT, specifically in CAFs, upregulates SAA expression and enhances the recruitment and differentiation of macrophages in the tumor microenvironment, thereby directly or indirectly promoting tumor progression and conferring resistance to immunotherapies in bladder cancer. |
| format | Article |
| id | doaj-art-e1f2e74b8b7f4d168b09a01f0d0429d9 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e1f2e74b8b7f4d168b09a01f0d0429d92025-08-20T02:02:20ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2024-009281NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancerJian Huang0Bo Wang1Dong Yan2Tianxin Lin3Lu Pei4Hao Yu5Wang He6Kaiwen Li7Meihua Yang8Weibin Hou9Honghui Zeng10Xin-Ke Zhang11Long Huang12Haide Qin13Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. ChinaInterventional Neuroradiology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, ChinaDepartment of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, P.R. ChinaDepartment of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, P.R. ChinaCollaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. ChinaDepartment of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, P.R. ChinaDepartment of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, P.R. ChinaDepartment of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, P.R. ChinaDepartment of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, P.R. ChinaDepartment of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, P.R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. ChinaDepartment of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P.R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. ChinaBackground This study comprehensively investigates the association between the expression of nicotinamide N-methyltransferase (NNMT) and clinical outcomes of urothelial bladder cancer (UBC), as well as the molecular mechanisms by which NNMT in cancer-associated fibroblast (CAF) modulates tumor progression and immunotherapy resistance in UBC.Methods Single-cell transcriptomic analyses, immunohistochemical and immunofluorescence assays were performed on bladder cancer samples to validate the relationship between NNMT expression and clinical outcomes. A series of experiments, including chromatin immunoprecipitation assay, liquid chromatography tandem mass spectrometry assay, and CRISPR‒Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9) knockout, together with in vivo models, have been established to determine the molecular functions of NNMT in CAFs in UBC.Results We demonstrated that elevated expression of the nicotinamide adenine dinucleotide (NAD+) metabolism enzyme NNMT in CAFs (NNMT+ CAFs) was significantly associated with non-response to programmed death-ligand 1 (PD-L1) blockade immunotherapy in patients with UBC and predicted the unfavorable prognosis of UBC in two independent large cohorts. Targeting NNMT using the inhibitor 5-Amino-1-methylquinolinium iodide significantly reduced tumor growth and enhanced the apoptotic effects of the anti-PD-L1 antibody in UBC mouse models. Mechanistically, NNMT+ CAFs recruit tumor-associated macrophages via epigenetic reprogramming of serum amyloid A (SAA) to drive tumor cell proliferation and confer resistance to programmed death-1/PD-L1 blockade immunotherapy.Conclusions NNMT+ CAFs were significantly associated with non-response to PD-L1 blockade immunotherapy in patients with UBC. Elevated NNMT, specifically in CAFs, upregulates SAA expression and enhances the recruitment and differentiation of macrophages in the tumor microenvironment, thereby directly or indirectly promoting tumor progression and conferring resistance to immunotherapies in bladder cancer.https://jitc.bmj.com/content/12/7/e009281.full |
| spellingShingle | Jian Huang Bo Wang Dong Yan Tianxin Lin Lu Pei Hao Yu Wang He Kaiwen Li Meihua Yang Weibin Hou Honghui Zeng Xin-Ke Zhang Long Huang Haide Qin NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer Journal for ImmunoTherapy of Cancer |
| title | NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer |
| title_full | NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer |
| title_fullStr | NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer |
| title_full_unstemmed | NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer |
| title_short | NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer |
| title_sort | nad metabolism enzyme nnmt in cancer associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer |
| url | https://jitc.bmj.com/content/12/7/e009281.full |
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