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

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.

Glycosylation Alterations in Cancer Cells, Prognostic Value of Glycan Biomarkers and Their Potential as Novel Therapeutic Targets in Breast Cancer

“…Given the rate of PD-L1 presence in TNBC cells, targeting this mechanism is thought to bear good potential in TNBC treatment [ 39 , 71 , 72 ]. Another animal study supported this finding, namely that interference with glycosylation of PD-L1 leads to its loss of function and in turn increases the efficacy of immunotherapy and radiotherapy in TNBC [ 73 ]. A combinatorial treatment with epidermal growth factor receptor (EGFR) inhibitor gefitinib and a saccharide analogue, 2-deoxy-D-glucose can enhance antitumor immunity in murine model of TNBC by deglycosylation of PD-L1 [ 74 ].…”

Tumor Selective Metabolic Reprogramming as a Prospective PD‐L1 Depression Strategy to Reactivate Immunotherapy

“…To test whether the PD‐L1 down‐regulation would affect PD‐1 binding, we incubated tumor cells with recombinant mouse PD‐1 (CD279) Fc protein. [ 19 ] Immunofluorescence showed that IR‐LND@Alb remarkably reduced PD‐1 binding to tumor cells (Figure 3G and Figure S25B, Supporting Information). Furthermore, we evaluated the efficacy of IR‐LND@Alb on T‐cell‐mediated tumor cell killing.…”

Metabolic clogging of mannose triggers genomic instability via dNTP loss in human cancer cells

“…Given the homeostatic role and ubiquitous expression of MPI (Proudfoot et al, 1994), supraphysiological concentrations of mannose are required to trigger its anti-cancer activity in a wide variety of cancer cells (Gonzalez et al, 2018; Zhang et al, 2022). This limitation may hamper the possible clinical use of mannose in cancer therapy.…”