Scientific Paper Report

Discoveries in the field of science often have significant implications for understanding natural phenomena and improving practical applications. Recently, a research paper published in Science Immunology titled “Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos” (April 19, 2024, Sci. Immunol. 9, eadg8817) revealed the impact of serine enrichment in tumors on the accumulation of regulatory T cells (Treg cells) and anti-tumor immunity. This report will provide a detailed introduction to the study’s background, methods, results, and significance.

Research Background

Previous studies have shown that T cell-based immunotherapy methods have great potential in cancer treatment. However, due to the immunosuppressive nature of the tumor microenvironment (TME), the effects of existing immunotherapies are limited. CD4+ regulatory T cells (Treg cells), through the expression of the transcription factor FoxP3, can inhibit antitumor immune responses. Temporarily eliminating Treg cells can reduce tumor growth. Therefore, understanding how Treg cells differentiate and accumulate in the TME is crucial for lifting immunosuppression within the TME and bringing more effective immunotherapies into application.

The nutrient profile in the TME is significantly different from that in non-cancerous tissues. Ample evidence suggests that changes in the nutrient profile impact anti-tumor T cell responses. Thus, systematic, large-scale, and unbiased quantitative studies of metabolites in the TME are necessary to identify immunosuppressive metabolites and reveal potential metabolic pathways, serving as new targets to stimulate anti-tumor immune responses.

Source of the Study

The study was collaboratively completed by several scientists, including Ma Sicong, Roger Sandhoff, Xiu Luo, and others, involving research institutions such as the School of Basic Medicine at the University of Science and Technology of China, the German Cancer Research Center, and the State Key Laboratory of Reproductive Medicine at Nanjing Medical University. The research results were published in Science Immunology on April 19, 2024.

Research Process

Metabolomic Analysis

The study first measured 630 metabolites in the tumor interstitial fluid (TIF) and plasma of mice carrying B16 melanoma, murine melanoma, and MC-38 colorectal tumors using the Biocrates MXP Quant 500 kit (Figure 1, a to c). The major metabolic groups included fatty acids and their related substances, sphingolipids, phospholipids, etc. Principal component analysis (PCA) and heatmap analysis revealed that certain amino acids and lipids, such as sphingolipids, in TIF samples were significantly higher than in plasma samples, suggesting enrichment of substrates for the sphingolipid synthesis metabolic pathway in the TME.

Sphingolipid Synthesis Pathway and Treg Cell Accumulation

Next, the study used Treg cell-specific Sptlc2-deficient mice (Sptlc2fl/flFoxp3yfp-cre) and a serine-free diet feeding strategy. The results showed that serine enrichment promotes Treg cell accumulation in the TME through an Sptlc2-dependent mechanism, and inhibition of serine or deletion of Sptlc2 significantly reduced Treg cell accumulation.

Mechanism of Specific Metabolites

Further analysis revealed an intermediate metabolite called sphinganine, which can directly bind to the transcription factor c-Fos, promoting the transcription of target genes (e.g., PDCD1, encoding PD-1), thereby increasing Treg cell differentiation in vitro. PD-1 is c-Fos dependent, and c-Fos, as a partner with c-Jun, cooperates with NFAT1 and NFAT2 in the pdcd1 promoter region to influence PD-1 protein expression.

Cellular Function and Tumor Suppression

Further studies showed that tumor growth was significantly inhibited in mice with Treg cell-specific deletion of Sptlc2. These results demonstrated the critical role of Sptlc2 in Treg cell accumulation and tumor immune suppression. Notably, by analyzing c-Fos expression in the tumor microenvironment, c-Fos increases the expression of FoxP3 by promoting the expression of the PDCD1 gene, enhancing Treg cell differentiation.

Research Results and Significance

Major Findings

The study revealed that the enrichment of serine and palmitic acid in the TME can promote Treg cell accumulation in the TME through an Sptlc2-dependent sphingolipid synthesis pathway. Specifically, sphinganine, as a second messenger molecule, can convert external metabolic information in the TME into nuclear signals, thereby promoting Treg cell differentiation.

Scientific Value and Application Prospects

This discovery provides new insights into the mechanisms of immunosuppression in the tumor microenvironment and offers new targets for future cancer immunotherapy. Regulating serine and sphingolipid synthesis pathways could open new immunotherapy methods, improving the effectiveness of tumor treatment.

Research Highlights

1. Discovery of Serine Enrichment and Sphinganine: Clearly identified serine and sphinganine in the TME, promoting Treg cell differentiation and accumulation through the sphingolipid synthesis pathway.
2. Relationship Between c-Fos and Treg Cell Differentiation: Revealed the crucial role of c-Fos through its impact on PDCD1 transcription in Treg cell-related responses.
3. Innovative Experimental Methods: Employed various high-throughput techniques such as metabolomic analysis, single-cell RNA sequencing (scRNA-seq), and CUT&RUN sequencing, accurately analyzing metabolic changes in the TME and their impact on regulatory immune functions.

Additional Information

The study also suggests further research directions, such as whether similar metabolite enrichment exists in the human TME and how to translate these findings into clinical treatment strategies. Additionally, understanding the roles of other relevant serine metabolic pathways in the TME will be an important direction for future research.

Through comprehensive and systematic research, this paper provides a valuable scientific basis for understanding complex metabolism and immune regulation in the tumor microenvironment.