The Tumor Lactate-SREBP2 Signaling Pathway Drives Tolerogenic Dendritic Cell Maturation and Promotes Cancer Progression

In recent years, the critical role of dendritic cells (DCs) in antitumor immunity has been widely recognized. However, many cancers cause DC dysfunction through mechanisms that are not fully understood. In a newly published study in this field, researchers Michael P. Plebanek and others delve into the functional changes of DCs in the tumor microenvironment (TME) and reveal the important role of the lactate-SREBP2 signaling axis in the tolerogenic maturation of dendritic cells. This study, collaboratively completed by multiple departments at Duke University’s Cancer Research Institute, was published in the May 10, 2024 issue of Science Immunology.

Research Background

Dendritic cells play a core role in presenting tumor antigens and activating naive T cells. However, many cancers are accompanied by dysfunctional DCs that cannot effectively activate CD8+ T cells. Increasing research shows that inhibitory DCs are characterized by a decrease in antigen cross-presentation and a tendency to induce regulatory T cells (Tregs). However, the mechanisms underlying the formation and function of these inhibitory DCs remain unclear.

The goal of this study is to elucidate the specific mechanisms by which lactate and the SREBP2 signaling pathway regulate the tolerogenic maturation of DCs in the tumor microenvironment and to explore new strategies to reverse the inhibitory functions of these DCs by intervening in this signaling pathway to enhance antitumor immunity.

Research Methods

Researchers employed various advanced technologies, including single-cell RNA sequencing (scRNA-seq), single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq), and Fluorescence-Activated Cell Sorting (FACS). Using these technologies, they conducted detailed gene expression and epigenetic analyses of DCs from tumor-draining lymph nodes (TDLNs) and non-draining lymph nodes (NDLNs).

Research Process

1. Single-Cell RNA Sequencing: By performing scRNA-seq on DCs under different conditions (tumor-draining lymph nodes, non-draining lymph nodes, and lymph nodes unaffected by the tumor), the researchers identified a specific DC population enriched with immunoregulatory molecules and mevalonate pathway genes.
2. Unrevealed SREBP2 Target Genes: Using scATAC-seq, the researchers discovered specific chromatin-accessible regions enriched with SREBP binding sites that were specifically open in the inhibitory DC population.
3. Flow Cytometry Validation: Through flow cytometry, the researchers validated the protein expression levels of the above-mentioned gene expression features in specific DC subgroups.

Data Analysis

The research team used various algorithms and tools for data analysis, including heatmaps for gene expression characteristics, Gene Set Enrichment Analysis (GSEA), and chromatin accessibility trajectory analysis. Through these analyses, the researchers detailed the mechanism by which lactate promotes the tolerogenic maturation of DCs by activating the SREBP2 signaling pathway.

Major Findings

CD63+ mregDCs

The researchers identified CD63 as a unique surface marker that can distinguish DCs with mature immunoregulatory properties (mregDCs) from other conventional DCs (cDCs). These CD63+ mregDCs significantly accumulate in tumor-draining lymph nodes and exhibit high immunosuppressive function.

Metabolic Characteristics

The study showed that CD63+ mregDCs rely on fatty acid oxidation (FAO) for energy metabolism, with significantly enhanced expression of mevalonate pathway genes. This metabolic feature is closely related to the immunosuppressive function of these DCs, as increased fatty acid metabolism promotes the activity of phenylpyruvate and IDO1, thereby driving Treg differentiation.

Lactate-SREBP2 Signaling Axis

Experiments demonstrated that lactate can activate SREBP2 under acidic conditions (pH 6.8), leading to an increased expression of a series of mevalonate pathway genes. This finding further supports the mechanism by which lactate promotes the development of mregDCs through the SREBP2 signaling pathway in the TME.

Intervention Strategies

The team inhibited SREBP2 using gene knockdown and pharmacological methods, significantly enhancing CD8+ T cell antitumor activity and inhibiting melanoma progression. For example, using the SREBP inhibitor Fatostatin reduced the proportion of CD63+ mregDCs and increased the number of tumor-infiltrating CD8+ T cells, thereby inhibiting tumor growth.

Research Significance

This study reveals the critical role of the lactate-SREBP2 signaling pathway in the immunosuppressive maturation of dendritic cells, expanding the understanding of how tumors evade immune surveillance through metabolic pathways. Targeting this signaling axis can effectively reverse tumor-induced immune tolerance, enhancing the efficacy of immunotherapy and providing new ideas and targets for cancer treatment.

Research Highlights

1. CD63 mregDC Marker: Identification of CD63 as a specific marker helps recognize and isolate dendritic cells with immunoregulatory functions.
2. Metabolic Pathways: The revelation of the specific metabolic characteristics of mregDCs in fatty acid oxidation and the mevalonate pathway.
3. Lactate-SREBP2 Axis: For the first time, the key role of lactate in mregDCs maturation through SREBP2 signaling is revealed, showing the immunoregulatory mechanism of lactate in the TME.
4. Therapeutic Targeting: Targeting SREBP2 can significantly inhibit the immunosuppressive function of mregDCs, thereby enhancing antitumor immune responses.

These research results emphasize the importance of metabolic signaling pathways in the tumor microenvironment in regulating immune cell function, providing strong theoretical and experimental support for future therapeutic strategies that modulate DC immune functions through metabolic pathways.