Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) are key regulators of antitumor immunity.
• Checkpoint blockade immunotherapies targeting PD-1/PD-L1 show limited efficacy in breast cancer.
• The precise role of PD-L1 in different tissue compartments, particularly adipose tissue, remains unclear.

Purpose of the Study:

• To investigate the role of PD-L1 expressed by adipocytes in modulating the efficacy of anti-PD-1/PD-L1 immunotherapy.
• To explore the potential of targeting adipogenesis to enhance antitumor immunity in breast cancer.

Main Methods:

• Compared PD-L1 expression in mature adipocytes and preadipocytes.
• Assessed the impact of adipocyte PD-L1 on CD8+ T cell function in vitro.
• Utilized genetic ablation and forced expression of PD-L1 in adipocytes/preadipocytes.
• Administered pharmacologic inhibitors of adipogenesis in mouse models of breast cancer.

Main Results:

• PD-L1 expression is significantly higher in mature adipocytes compared to preadipocytes.
• Adipocyte-derived PD-L1 inhibits anti-PD-L1 antibody-mediated activation of CD8+ T cells.
• Ablation of adipocyte PD-L1 restored T cell antitumor functions, while forced preadipocyte PD-L1 expression induced inhibition.
• Inhibition of adipogenesis reduced adipose tissue PD-L1 levels and enhanced the efficacy of anti-PD-1/PD-L1 therapies in vivo.

Conclusions:

• Adipose tissue PD-L1 represents a significant barrier to effective anti-PD-1/PD-L1 immunotherapy in breast cancer.
• Targeting adipogenesis offers a novel strategy to overcome PD-L1-mediated immune suppression and improve immunotherapy outcomes.
• Adipose tissue plays a crucial, previously unrecognized role in breast cancer progression and immune evasion.