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Published on: June 9, 2023
DHDH-mediated D-xylose metabolism induces immune evasion in triple-negative breast cancer
Huai-Liang Wu1, Yue Gong2, Yun-Xiao Ling2
1Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, China.
Background:
Although the prognosis of triple-negative breast cancer (TNBC) has significantly improved in the era of immunotherapy, many TNBC patients are resistant to therapies, and their disease progresses rapidly. Deciphering the metabolic mechanisms regulating anticancer immunity will provide new insights into therapeutic strategies for TNBC.
Methods:
In this study, we performed bioinformatics analysis in our multi-omics TNBC database and identified that a metabolic enzyme, dihydrodiol dehydrogenase (DHDH), might promote the phenotype of "cold tumor" in TNBC. The biological function of DHDH was verified by in vitro and in vivo functional experiments, and the potential molecular mechanism of DHDH promoting TNBC immune escape was further explored.
Findings:
Mechanistically, DHDH mediated the synthesis and depletion of the substrate D-xylose and inhibited the activation of the proteasome subunit beta type 9 (PSMB9) and further induction of the immune response. We demonstrated that D-xylose supplementation could enhance the proliferation of CD8+ T cells and the expression of cytotoxic markers against cocultured DHDH-wild type (WT) cells. Consistently, D-xylose supplementation in vivo promoted CD8+ T cell infiltration and the expression of cytotoxic markers and increased the sensitivity of DHDH-overexpressing tumors to immune checkpoint blockade (ICB).
Conclusions:
Our findings reveal that a D-xylose-regulated PSMB9-dependent pathway governs tumor-intrinsic immunogenicity and, hence, the sensitivity to ICB, which may provide approaches to promote the "cold-to-hot" transition in TNBC.
Funding:
This study was funded by the National Key Research and Development Plan of China, Shanghai Science and Technology Commission, National Natural Science Foundation of China, and China Postdoctoral Science Foundation.
Insights
Dihydrodiol dehydrogenase (DHDH) drives triple-negative breast cancer immune evasion by depleting D-xylose. Supplementing D-xylose can enhance T-cell responses and improve immunotherapy effectiveness in TNBC.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- Triple-negative breast cancer (TNBC) shows resistance to immunotherapy, necessitating research into underlying resistance mechanisms.
- Understanding metabolic regulation of anticancer immunity is crucial for developing novel TNBC therapeutic strategies.
Purpose of the Study:
- To investigate the role of dihydrodiol dehydrogenase (DHDH) in TNBC immune escape.
- To elucidate the metabolic mechanisms by which DHDH influences the tumor microenvironment and immunotherapy response.
Main Methods:
- Bioinformatics analysis of a multi-omics TNBC database to identify key metabolic enzymes.
- In vitro and in vivo functional experiments to validate the role of DHDH.
- Exploration of the molecular mechanism involving D-xylose and proteasome subunit beta type 9 (PSMB9).
Main Results:
- DHDH was identified as a metabolic enzyme promoting a "cold tumor" phenotype in TNBC.
- DHDH mediates D-xylose metabolism, inhibiting PSMB9 activation and immune response induction.
- D-xylose supplementation enhanced CD8+ T-cell proliferation and cytotoxic marker expression, increasing tumor sensitivity to immune checkpoint blockade (ICB).
Conclusions:
- A D-xylose-regulated, PSMB9-dependent pathway controls tumor-intrinsic immunogenicity in TNBC.
- This pathway influences sensitivity to ICB, offering potential strategies for "cold-to-hot" tumor transition in TNBC.
