QDPR Deficiency Drives Immune Suppression in Pancreatic Cancer

Medical Laboratory Science Biochemistry Basic Medical Sciences Life Sciences Immunology Oncology Medicine Cell Biology
QDPR deficiency pancreatic cancer immune suppression biopterin metabolism ICB therapy

Background

Pancreatic Ductal Adenocarcinoma (PDAC) is a malignancy with a highly immunosuppressive tumor microenvironment (TME), showing strong resistance to immune checkpoint blockade (ICB) therapies, such as anti-PD-1 and anti-CTLA-4 treatments. Myeloid-Derived Suppressor Cells (MDSCs) derived from tumors play a critical role in tumor immune suppression, leading to ICB resistance in cancers including PDAC. Unveiling this immunosuppressive mechanism will provide new strategies to enhance the effectiveness of ICB therapy. Biopterin metabolism influences the immune environment of tumors, and the absence of a key enzyme in the biopterin metabolism pathway, dihydropteridine reductase (QDPR), may contribute to ICB resistance.

Source of the Paper

The paper is authored by multiple researchers including Ji Liu, Xiaowei He, and Shuang Deng from several research institutions such as the Sun Yat-sen University Cancer Center and the Guangdong Provincial Clinical Research Center. The paper was published in the journal Cell Metabolism on May 7, 2024.

Research Workflow

In this study, the authors investigated how QDPR deficiency leads to immunosuppression and ICB therapy resistance in pancreatic cancer through the biopterin metabolism pathway.

  1. Establishment of Cell and Animal Models

    • A gene knockout mouse model was established: using an adeno-associated virus (AAV)-shQDPR system to specifically knock down the expression of QDPR in the pancreas.
    • Human and mouse pancreatic cancer cell lines were established: employing CRISPR/Cas9 technology for QDPR gene knockout and overexpression.

  2. Metabolic and Immune Characterization

    • Investigated how QDPR deficiency causes an accumulation of dihydrobiopterin (BH2) in pancreatic cancer cells, reducing the tetrahydrobiopterin (BH4)/BH2 ratio, affecting nitric oxide synthase function, and leading to increased reactive oxygen species (ROS) levels.
    • Analyzed the impact of QDPR deficiency on MDSCs and CD8+ T cells within the tumor microenvironment.

  3. Gene Expression and Epigenome Analysis

    • Single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation (ChIP) techniques were used to analyze the expression of immunosuppressive molecules and epigenomic changes, with a particular focus on the changes in the distribution of H3K27me3 and its regulatory role on CXCL1 gene expression.

  4. Tumor Immunity and ICB Treatment Efficacy

    • Explored whether BH4 supplementation could restore the BH4/BH2 ratio, enhance antitumor immunity, and overcome ICB resistance induced by QDPR deficiency.

Main Research Findings

  1. QDPR Deficiency and Pancreatic Cancer Prognosis

    • QDPR expression levels are significantly lower in pancreatic cancer patients compared to normal tissues, and its expression levels are negatively correlated with patients’ pathological grading and survival time.
    • In QDPR knockout mouse models, tumor growth accelerated, with significant increases in Pancreatic Intraepithelial Neoplasia (PanIN) lesions and myeloid cells, while CD8+ T cells significantly decreased.

  2. Establishment of an Immunosuppressive Microenvironment

    • QDPR deficiency leads to an accumulation of immunosuppressive MDSCs in the tumor microenvironment and a dysfunction of CD8+ T cells, primarily dependent on the CXCL1/CXCR2 axis. Pancreatic cancer cells deficient in QDPR secrete CXCL1 to recruit more MDSCs, thereby suppressing antitumor immune responses.

  3. Epigenomic Regulation

    • The accumulation of BH2 induced by QDPR deficiency induces ROS generation, reducing H3K27me3 distribution on the CXCL1 promoter, leading to an upregulation of CXCL1 gene expression. Epigenomic and chromatin openness analyses show that QDPR deficiency significantly reduces H3K27me3 levels at the CXCL1 promoter and increases chromatin openness.

  4. ICB Therapy Resistance

    • QDPR-deficient PDAC shows significant resistance to ICB therapy. This is mainly attributed to the accumulation of MDSCs and the reduction and functional inhibition of CD8+ T cells.

  5. Therapeutic Effects of BH4 Supplementation

    • BH4 supplementation can restore the BH4/BH2 ratio imbalance caused by QDPR deficiency, reduce ROS generation, increase H3K27me3 levels, suppress CXCL1 expression, reduce the recruitment of MDSCs, increase the number and function of CD8+ T cells, and thereby overcome ICB therapy resistance.
    • Combined treatment with BH4 and ICB in mouse models demonstrated significant antitumor effects, significantly suppressing the growth of QDPR-deficient PDAC and significantly prolonging the survival time of mice.

Conclusion

The study shows that QDPR deficiency, by affecting the biopterin metabolism pathway, induces ROS generation and epigenomic changes, leading to immunosuppression and ICB therapy resistance in pancreatic cancer. BH4 supplementation can restore BTM, enhancing antitumor immune responses and overcoming ICB resistance. This study provides new strategies for improving the efficacy of ICB therapy and suggests that QDPR can be used as a predictive biomarker for ICB treatment.

Research Highlights

  • QDPR deficiency in pancreatic cancer is associated with poor prognosis.
  • The BH4/BH2 ratio imbalance caused by QDPR deficiency affects H3K27me3 levels through ROS generation, promoting CXCL1 expression, recruiting MDSCs, and inhibiting CD8+ T cell function.
  • BH4 supplementation therapy can reverse the immunosuppression caused by QDPR deficiency, enhancing the efficacy of ICB therapy.
  • Proposed QDPR as a predictive biomarker for ICB therapy and provided a new combination therapy strategy with BH4 supplementation.

This research provides a new perspective on immunotherapy for pancreatic cancer and offers scientific support for the development of future therapeutic strategies.