Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression

Area of Science:

• Immunology
• Oncology
• Cancer immunotherapy

Background:

• The programmed death-1 receptor (PD-1) and its ligand (PD-L1) pathway is a key target in cancer immunotherapy.
• The precise roles of host versus tumor PD-L1/PD-1 signaling in therapeutic response remain unclear.

Purpose of the Study:

• To elucidate the mechanistic contribution of host and tumor PD-L1/PD-1 signaling to the efficacy of PD-1/PD-L1 blockade therapy.
• To identify the specific immune cell types expressing PD-L1 that influence treatment outcomes.

Main Methods:

• Utilized three distinct tumor-bearing mouse models with varying sensitivities to PD-L1 blockade.
• Generated and analyzed PD-L1 and PD-1 knockout mouse models.
• Assessed PD-L1 expression in tumor microenvironments and draining lymph nodes in both murine models and human cancer patients (ovarian cancer, melanoma).

Main Results:

• Loss of therapeutic efficacy in immunodeficient and PD-L1/PD-1 deficient mice, indicating a crucial role for host immune cells.
• No significant impact on PD-L1 blockade efficacy from tumor cell PD-L1 knockout or overexpression.
• High functional PD-L1 expression observed on dendritic cells and macrophages in both murine and human tumor microenvironments and associated lymph nodes.
• PD-L1 expression on dendritic cells and macrophages correlated with treatment efficacy in ovarian cancer and melanoma patients receiving anti-PD-1 or anti-PD-1/anti-CTLA-4 therapy.

Conclusions:

• Host immune cells, particularly dendritic cells and macrophages, are critical for the therapeutic efficacy of PD-1/PD-L1 blockade.
• Tumor cell PD-L1 expression does not determine the efficacy of this immunotherapy.
• PD-L1 expression on dendritic cells and macrophages serves as a potential biomarker for predicting clinical response to PD-1/PD-L1 blockade.