Glioma is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that severely limits immune checkpoint blockade efficacy. Glioma-associated myeloid cells (GAMs), including resident microglia and infiltrating macrophages, constitute the dominant immune population within gliomas and shape antitumor immune responses. While immune checkpoint pathways have been extensively studied in T lymphocytes, the contribution of myeloid-restricted immune checkpoints to glioma progression remains poorly defined. Programmed death-1 homolog (PD-1 H/VISTA) is an inhibitory immune checkpoint predominantly expressed by myeloid cells, yet its functional role in GAMs has not been systematically investigated. PD-1 H expression in human glioma was analyzed using immunohistochemistry, bulk transcriptomic datasets, and single-cell RNA sequencing. Associations between PD-1 H expression, immune cell composition, and patient survival were evaluated in clinical cohorts. The functional role of PD-1 H in GAMs was examined using genetically manipulated myeloid cells in vitro and orthotopic glioma mouse models in vivo. Transcriptomic profiling was performed to identify PD-1 H-associated biological pathways. The therapeutic potential of PD-1 H blockade was assessed using monoclonal antibody treatment in glioma-bearing mice. PD-1 H was highly expressed in human glioma tissues and was predominantly enriched in GAMs. Elevated PD-1 H expression was associated with an immunosuppressive tumor microenvironment characterized by increased infiltration of immunosuppressive myeloid populations, reduced cytotoxic T-cell presence, elevated expression of multiple immune checkpoint molecules, and unfavorable clinical outcomes. Functionally, PD-1 H promoted immunosuppressive myeloid polarization, enhanced malignant behaviors of glioma cells, and suppressed CD8 + T-cell proliferation in vitro. In orthotopic glioma models, PD-1 H expression in GAMs accelerated tumor progression, promoted T-cell exhaustion, and shortened survival, whereas PD-1 H deficiency restrained tumor growth and prolonged survival. Mechanistic studies revealed that the AKT/NF-κB pathway mediates PD-1 H-dependent myeloid reprogramming. Importantly, therapeutic blockade of PD-1 H significantly suppressed glioma growth and improved survival in vivo. PD-1 H functions as a myeloid-restricted immune checkpoint that drives immunosuppressive reprogramming of glioma-associated myeloid cells, promotes glioma progression, and impairs antitumor T-cell immunity. Targeting PD-1 H represents a promising myeloid-focused immunotherapeutic strategy to overcome immune suppression in glioma.
Guo et al. (Sun,) studied this question.