Upregulation of HLA‐II related to LAG‐3+CD4+ T cell infiltration is associated with patient outcome in human glioblastoma

Abstract Glioblastoma (GBM) is the most common malignant diffuse glioma of the brain. Although immunotherapy with immune checkpoint inhibitors (ICIs), such as programmed cell death protein (PD)‐1/PD ligand‐1 inhibitors, has revolutionized the treatment of several cancers, the clinical benefit in GBM patients has been limited. Lymphocyte‐activation gene 3 (LAG‐3) binding to human leukocyte antigen‐II (HLA‐II) plays an essential role in triggering CD4 + T cell exhaustion and could interfere with the efficiency of anti‐PD‐1 treatment; however, the value of LAG‐3–HLA‐II interactions in ICI immunotherapy for GBM patients has not yet been analyzed. Therefore, we aimed to investigate the expression and regulation of HLA‐II in human GBM samples and the correlation with LAG‐3 + CD4 + T cell infiltration. Human leukocyte antigen‐II was highly expressed in GBM and correlated with increased LAG‐3 + CD4 + T cell infiltration in the stroma. Additionally, HLA‐II High LAG‐3 High was associated with worse patient survival. Increased interleukin‐10 (IL‐10) expression was observed in GBM, which was correlated with high levels of HLA‐II and LAG‐3 + T cell infiltration in stroma. HLA‐II High IL‐10 High GBM associated with LAG‐3 + T cells infiltration synergistically showed shorter overall survival in patients. Combined anti‐LAG‐3 and anti‐IL‐10 treatment inhibited tumor growth in a mouse brain GL261 tumor model. In vitro, CD68 + macrophages upregulated HLA‐II expression in GBM cells through tumor necrosis factor‐α (TNF‐α). Blocking TNF‐α‐dependent inflammation inhibited tumor growth in a mouse GBM model. In summary, T cell–tumor cell interactions, such as LAG‐3–HLA‐II, could confer an immunosuppressive environment in human GBM, leading to poor prognosis in patients. Therefore, targeting the LAG‐3–HLA‐II interaction could be beneficial in ICI immunotherapy to improve the clinical outcome of GBM patients.