Folate metabolism in tumor-associated macrophages drives immunosuppressive function to promote tumor growth
The study suggests that targeting the folate receptor beta in tumor-associated macrophages may alter their immunosuppressive function and slow tumor growth, but more research is needed to confirm these effects in humans.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study investigates the role of folate metabolism in tumor-associated macrophages (TAMs) and its impact on tumor growth. The researchers utilized a Folr2-/- mouse model to assess the effects of TAMs lacking the folate receptor beta (FRβ). They found that the absence of FRβ slowed tumor growth and altered the immune response.
Abstract
Tumor-associated macrophages (TAMs) promote tumor growth, inhibit effector lymphocytes, and induce resistance to immune checkpoint inhibitors (ICI). Therapies designed to deplete TAMs have had little success in the clinic, and strategies aimed to repolarize immunosuppressive TAMs to pro-inflammatory states have struggled with systemic toxicity. We have identified that the combination of low folate in the tumor microenvironment and TAM dependency on the high affinity folate receptor beta (FRβ) for folate uptake results in a unique metabolic dependency of TAMs necessary for their immunosuppressive function. FRβ (encoded by Folr2) is uniquely expressed on myeloid cells and upregulated on TAMs. FRβ+ TAMs exhibit an immunosuppressive phenotype in melanoma and are associated with worse clinical outcomes and resistance to ICI in melanoma patients. We generated a novel Folr2-/- mouse model to study why TAMs express a unique folate receptor and showed that tumor growth was slowed in the absence of Folr2 in a T-cell dependent manner. We observed a dramatic repolarization of Folr2-/- TAMs in vivo to pro-inflammatory states, resulting in increased cytotoxic T cell and NK cell infiltration into tumors. Importantly, we show that folate is low in the tumor microenvironment by performing metabolomics on melanoma tumors and adjacent normal tissue from warm autopsy patient specimens, and that we could increase tumor growth in Folr2-/- mice by increasing serum folate to supraphysiologic concentrations with a high folate diet. Integrated metabolomics and transcriptomic analysis demonstrated that Folr2-/- macrophages have impaired folate uptake and 1C metabolism-based reduction of oxidized glutathione in low folate conditions, resulting in increased mitochondrial reactive oxygen species (ROS) in Folr2-/- cells. Excess ROS results in leakage of mitochondrial DNA into the cytoplasm, activating cGAS-STING signaling and promoting pro-inflammatory macrophage polarization through TBK1 and NF-kB. Together, our data demonstrate that TAM expression of FRβ promotes their immunosuppressive functions by maintaining folate uptake in the low folate tumor microenvironment, suggesting that FRβ is a novel metabolic checkpoint on TAMs.
Background
This paper addresses the metabolic role of folate in tumor-associated macrophages (TAMs) and their contribution to tumor growth and immune suppression. Prior research has shown that TAMs promote tumor growth and inhibit immune responses, but the specific metabolic pathways involved have not been fully elucidated. Understanding the mechanisms by which TAMs operate could inform future therapeutic strategies aimed at repolarizing these cells.
Methods
The study utilized a Folr2-/- mouse model to investigate the effects of folate metabolism on TAM function and tumor growth. The primary outcome measured was tumor growth in the absence of Folr2, with secondary outcomes including immune cell infiltration and metabolic profiling. The study involved metabolomics and transcriptomic analyses of melanoma tumors and adjacent normal tissue.
Results
The absence of Folr2 in TAMs resulted in slowed tumor growth, indicating a T-cell dependent mechanism. Additionally, the study found that increasing serum folate levels in Folr2-/- mice led to increased tumor growth. Folr2-/- macrophages showed impaired folate uptake and increased mitochondrial ROS, which may contribute to their altered function.
Interpretation
These findings suggest that the expression of FRβ in TAMs is critical for their immunosuppressive function and tumor-promoting capabilities. While the study provides insights into the metabolic dependencies of TAMs, the clinical significance of these findings remains uncertain. The reliance on a mouse model and the potential for small effect sizes limit the generalizability of the results to human populations.
Key findings
- Tumor growth was slowed in Folr2-/- mice, indicating a T-cell dependent mechanism.
- Increased serum folate to supraphysiologic concentrations with a high folate diet increased tumor growth in Folr2-/- mice.
- Folr2-/- macrophages exhibited increased mitochondrial reactive oxygen species (ROS) due to impaired folate uptake.
- FRβ+ TAMs are associated with worse clinical outcomes and resistance to immune checkpoint inhibitors in melanoma patients.
- Integrated metabolomics and transcriptomic analysis demonstrated that Folr2-/- macrophages have impaired folate uptake.
Limitations
- Study relies on a mouse model, which may not fully replicate human biology.
- Findings are based on metabolomics and transcriptomic analyses, which may not directly translate to clinical outcomes.
- Potential small effect sizes limit generalizability.
- Short follow-up period may not capture long-term effects.