Macroscopic and Microscopic Mechanisms of Nicotinamide Metabolism Antagonism: Manipulation of the Gastric Cancer Microenvironment

Background Introduction

Gastric cancer (GC) is a type of cancer characterized by a unique and heterogeneous tumor microenvironment (TME). Despite advances in immune checkpoint blockade (ICB) therapy for gastric cancer, nearly half of the patients do not respond to ICB treatment. This suggests that the anti-tumor response is actually the result of multifactorial interactions within the TME.

To elucidate these complex interactions, the authors of this paper conducted a series of studies. Through transcriptomic analysis and dynamic plasma sample analysis, they first proposed the “antagonistic” mechanism of nicotinamide (NAM) metabolism within the tumor microenvironment. This article focuses on the dynamic antagonism between macrophages and cancer-associated fibroblasts (CAFs) expressing the rate-limiting enzymes nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide N-methyltransferase (NNMT), thus regulating the function of CD8+ T cells.

Research Source

This paper was written by Jiang et al. from the Department of Oncology, Southern Hospital, Southern Medical University, with collaborative units including the Cancer Center of the Sixth Affiliated Hospital of South China University of Technology, the Department of Gastrointestinal Surgery of the First Affiliated Hospital of Guangzhou Medical University, the Institute of Medical Science of the University of Tokyo, and Nanzan Veterinary Medical Science University, among others. The study was published in the journal “Cell Metabolism” on August 6, 2024.

Research Process

Experimental Design and Steps

The research process of this paper is divided into the following major steps:

1. Evaluation of Metabolite Activity and its Prognostic Value: Using tumor samples from the Asian Cancer Research Group (ACRG) cohort and the PRJEB25780 dataset, nicotinamide (NAM) and 1-methylnicotinamide (MNAM) levels in plasma samples were measured via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The NAM/MNAM ratio was calculated, revealing that NAM is associated with better prognosis, while MNAM correlates with poorer prognosis.

2. Cell-Specific Expression of NAM Metabolism: Using single-cell RNA sequencing (scRNA-seq) and cell co-culture experiments, the interaction of NAM metabolism between macrophages and cancer-associated fibroblasts (CAFs) was revealed. Macrophages primarily express NAMPT, whereas CAFs primarily express NNMT.

3. Macrophage-Derived NAMPT Extracellular Vesicles (EVs): Through isolation and identification of EVs, it was found that macrophages secrete EVs containing NAMPT, capable of downregulating NNMT expression in CAFs. Further experiments showed that EVs inhibit NNMT expression via the Sirt1/NICD axis.

4. Regulation of T Cell Function by NAM Metabolism: When co-culturing macrophages with CAFs, it was observed that EVs could reverse the inhibitory effect of CAFs on CD8+ T cell function, enhancing the cytotoxicity of CD8+ T cells.

5. Animal Experiment Verification: Using a mouse gastric cancer model, self-injection with NAMPT-overexpressing macrophages or their EVs significantly suppressed tumor growth, significantly increased the NAM/MNAM ratio in plasma, and enhanced tumor-infiltrating CD8+ T cell activity.

Experimental Results

• Through the global metabolite activity score, a significant correlation between the NAM/MNAM ratio and the ICB response was found.
• Single-cell RNA sequencing revealed the specific expression of NAMPT and NNMT in macrophages and CAFs.
• EVs secreted by macrophages containing NAMPT downregulated NNMT expression in CAFs and acted via the Sirt1/NICD axis.
• After self-injection with NAMPT-overexpressing macrophages or their EVs, tumor growth was significantly inhibited, and CD8+ T cell activity was enhanced.

Conclusion

The study demonstrates that NAM metabolism has significant dual importance in the tumor microenvironment of gastric cancer. The metabolic antagonism between macrophages and CAFs affects the anti-tumor response by regulating CD8+ T cell function. NAMPT extracellular vesicles can restore T cell activity and enhance the efficacy of anti-PD-1 therapy, providing a new therapeutic strategy for gastric cancer patients. The NAM/MNAM ratio revealed in this study can serve as a metabolic biomarker for ICB response, providing a basis for the selection of personalized treatment.

Research Highlights

• Key Findings: Macrophages suppress NNMT expression in CAFs by secreting EVs containing NAMPT, promoting CD8+ T cell anti-tumor activity.
• Clinical Significance: The NAM/MNAM ratio as a metabolic biomarker for ICB response offers a new strategy for the individualized treatment of gastric cancer.
• Methodological Innovation: By combining transcriptomic analysis, single-cell RNA sequencing, and animal models, the study systematically analyzed the metabolic interactions in the gastric cancer tumor microenvironment.

Applicability of the Research

By revealing the crucial role of NAM metabolism in the anti-tumor response of gastric cancer, this research provides a novel approach to improving ICB efficacy. Future research should focus on further elucidating the role of NAM metabolism in other types of tumors and testing the practicality of the NAM/MNAM ratio as a biomarker in clinical trials.

Conclusion

This paper reveals the key role of macrophages and CAFs in the regulation of NAM metabolism through a systematic and comprehensive experimental process, providing new directions for ICB treatment strategies against gastric cancer. The research not only holds significant scientific value but also offers practical application prospects for clinical treatment.