Saccharide analog, 2-deoxy-d-glucose enhances 4-1BB-mediated antitumor immunity via PD-L1 deglycosylation

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to a lack of targeted therapies and poorer prognoses.
• Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade offers limited response rates in TNBC.
• PD-L1 glycosylation in TNBC contributes to protein stability and immunosuppressive function, representing a potential therapeutic target.

Purpose of the Study:

• To investigate a novel strategy for PD-L1 deglycosylation in TNBC.
• To evaluate the efficacy of combining a saccharide analog, 2-deoxy-d-glucose (2-DG), with gefitinib for PD-L1 targeting.
• To explore the potential of this combination therapy, along with 4-1BB antibody, in enhancing antitumor immunity in TNBC models.

Main Methods:

• Treatment of TNBC models with 2-deoxy-d-glucose (2-DG) and gefitinib to assess PD-L1 deglycosylation and function.
• Analysis of PD-L1 and PD-1 binding, as well as 4-1BB and 4-1BBL expression and binding.
• Combination therapy using 2-DG/gefitinib and a 4-1BB antibody in TNBC syngeneic murine models.

Main Results:

• 2-DG/gefitinib treatment effectively inhibited PD-L1 glycosylation and its immunosuppressive function.
• The combination therapy decreased PD-L1 protein expression and its binding to PD-1, without affecting 4-1BB/4-1BBL interactions.
• Combined treatment with 2-DG/gefitinib and 4-1BB antibody significantly enhanced antitumor immunity in preclinical TNBC models.

Conclusions:

• PD-L1 deglycosylation using 2-DG and gefitinib represents a viable strategy for TNBC immunotherapy.
• The combination of PD-L1 deglycosylation and 4-1BB stimulation offers a promising new immunotherapeutic approach for TNBC.
• This strategy holds potential for improving treatment outcomes in patients with triple-negative breast cancer.