1. Academic Validation
  2. D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1

D-mannose facilitates immunotherapy and radiotherapy of triple-negative breast cancer via degradation of PD-L1

  • Proc Natl Acad Sci U S A. 2022 Feb 22;119(8):e2114851119. doi: 10.1073/pnas.2114851119.
Ruonan Zhang 1 Yajing Yang 1 Wenjing Dong 1 Mingen Lin 1 Jing He 1 Xinchao Zhang 1 Tongguan Tian 2 Yunlong Yang 3 Kun Chen 4 Qun-Ying Lei 5 Song Zhang 6 Yanping Xu 7 Lei Lv 8
Affiliations

Affiliations

  • 1 Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 2 Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
  • 3 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 4 Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
  • 5 Fudan University Shanghai Cancer Center and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 6 Institute for Immunology and College of Life Sciences, Nankai University, Tianjin 300071, China [email protected] [email protected] [email protected].
  • 7 Tongji Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China; [email protected] [email protected] [email protected].
  • 8 Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; [email protected] [email protected] [email protected].
Abstract

Breast Cancer is the most frequent malignancy in women worldwide, and triple-negative breast Cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in Cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose-mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose-induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair-related genes, thereby sensitizing breast Cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.

Keywords

D-mannose; PD-L1; immunotherapy; radiotherapy; triple-negative breast cancer.

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