PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Tumor-infiltrating myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), are key components of the hypoxic tumor microenvironment.
• Immune checkpoints, such as programmed death-1 (PD-1) and its ligand PD-1 ligand 1 (PD-L1), play a critical role in regulating anti-tumor immune responses.

Purpose of the Study:

• To investigate the influence of hypoxia on immune checkpoint receptors and ligands expressed by MDSCs.
• To elucidate the molecular mechanisms underlying hypoxia-induced PD-L1 expression on MDSCs.
• To evaluate the therapeutic potential of targeting PD-L1 and hypoxia-inducible factor-1α (HIF-1α) in cancer immunotherapy.

Main Methods:

• Flow cytometry to analyze the expression of PD-L1, PD-L2, CD80, and CD86 on MDSCs.
• Hypoxia induction in tumor-bearing mice models.
• Chromatin immunoprecipitation and luciferase reporter assays to determine HIF-1α binding to the PD-L1 promoter.
• In vivo experiments involving blockade of PD-L1 and IL-10, and inhibition of HIF-1α.

Main Results:

• Hypoxia selectively and dramatically up-regulated PD-L1 on splenic MDSCs in tumor-bearing mice, with differential expression compared to tumor-site MDSCs.
• Hypoxia also increased PD-L1 expression on macrophages, dendritic cells, and tumor cells.
• PD-L1 up-regulation under hypoxia was dependent on HIF-1α, which directly binds to a hypoxia-response element in the PD-L1 promoter.
• Blockade of PD-L1 enhanced MDSC-mediated T cell activation and reduced IL-6 and IL-10 production by MDSCs.
• Neutralizing antibodies against IL-10 abrogated MDSC suppressive activity under hypoxia.

Conclusions:

• Hypoxia drives PD-L1 expression on MDSCs through HIF-1α, contributing to immune suppression in the tumor microenvironment.
• Targeting PD-L1 and HIF-1α simultaneously presents a promising novel strategy for enhancing cancer immunotherapy efficacy.
• Modulating cytokine production, such as IL-10, by MDSCs is crucial for their suppressive function under hypoxic conditions.