NAD + metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer.
Level 4 - case-series / case-control
Retrospective human cohort biomarker validation combined with preclinical animal and cell experiments
PubMed 39067875 · doi:10.1136/jitc-2024-009281
What was done
The authors analyzed the association between nicotinamide N-methyltransferase (NNMT) expression in cancer-associated fibroblasts (CAFs) and clinical outcomes in urothelial bladder cancer (UBC) across two patient cohorts using single-cell transcriptomics, immunohistochemistry, and immunofluorescence. Molecular mechanisms and therapeutic targeting were evaluated using chromatin immunoprecipitation, mass spectrometry, CRISPR-Cas9 knockout models, and in vivo UBC mouse models treated with an NNMT inhibitor (5-amino-1-methylquinolinium iodide) and anti-PD-L1 antibody.
What was found
Elevated NNMT expression in CAFs was significantly associated with non-response to PD-L1 blockade and predicted unfavorable prognosis in two UBC cohorts (specific effect sizes, survival times, and p-values not reported in abstract). Mechanistically, NNMT in CAFs drove macrophage recruitment via epigenetic upregulation of serum amyloid A (SAA). In mouse models, NNMT inhibition combined with anti-PD-L1 therapy significantly reduced tumor growth and enhanced apoptosis (quantitative values not reported in abstract).
Why it matters
The study identifies CAF-specific NNMT expression as a driver of immunotherapy resistance through macrophage recruitment in urothelial bladder cancer. Combining NNMT inhibitors with PD-L1 blockade represents a potential strategy to overcome immune checkpoint resistance.
Limits
The abstract does not provide sample sizes, patient characteristics, hazard ratios, or exact statistical metrics. Therapeutic efficacy data rely on preclinical animal models rather than human clinical trials.
Cited by
- partial 5-Amino-1MQ inhibits nicotinamide N-methyltransferase (NNMT), which preserves NAD levels.