Immunosuppression of HMOX1 contributes to metastasis and poor prognosis in glioma.

BACKGROUNDGlioma is the most prevalent form of brain cancer, characterized by immunosuppression and heterogeneity. Recently, numerous genes associated with immunosuppression have been identified in glioma. Nevertheless, the molecular mechanisms underlying this immunosuppression remain unclear. In this study, we aim to delineate the relationship between HMOX1 and cancer-related immunosuppression in glioma.

METHODSTwo GEO datasets were selected for assessment the expression of HMOX1. The Chinese Glioma Genome Atlas (CGGA, 693 patients) and the Cancer Genome Atlas (TCGA, 702 patients) were analyzed using R software. Additionally, single-cell RNA sequencing (scRNA-seq) data from CGGA were also analyzed. Cell experiments and xenograft model were carried out to validate the role of HMOX1 in glioma metastasis.

RESULTSTwo GEO datasets revealed a significantly increased expression of HMOX1 in glioma. This upregulation of HMOX1 was associated with WHO grade 4, IDH wild-type, 1p/19q non-codeletion, and poor survival in both CGGA and TCGA datasets. GO, KEGG, and GSVA analyses indicated that immune-related pathways were the most dysregulated processes. We observed infiltration of M2 macrophages and activation of checkpoint genes in HMOX1-upregulated glioma. ScRNA-seq analysis showed that HMOX1 was upregulated in M2 macrophages, indicating the association between HMOX1 upregulation and polarization of M2 macrophages. Knockdown HMOX1 reduced the growth and metastasis of glioma cells in vitro and in vivo. Co-cultured HMOX1-inhibited M2 macrophages with glioma cells decreased the invasive ability of glioma cells.

CONCLUSIONIn glioma, high expression of HMOX1 was associated with cancer-related immunosuppression through polarization of M2 macrophages. Moreover, knockdown HMOX1 reduced the growth and metastasis of tumor cells in vitro and in vivo. These findings suggested that HMOX1 could serve as a prognostic factor for glioma.