Glioma is the most common primary intracranial tumor and has a high mortality rate. Traditional surgery combined with radiotherapy and chemotherapy did not significantly improve the prognosis of glioma patients, making the new clinical therapeutic methods to be urgently needed.
Studies have shown that tumor immune microenvironment plays a vital role in tumorigenesis and progression, giving rise to the emerging immunotherapy which has achieved marked success in the clinical treatment of tumors. For instance, cellular immunotherapy as chimeric antigen receptor T cell therapy (CAR-T) has a significant effect on patients with lymphoma and leukemia [28, 29]. The immune checkpoint inhibitors, especially monoclonal antibodies against PD-1/PDL-1 and CTLA-4 have been approved by the FDA for the first-line treatment of melanoma , non-small-cell lung cancer (NSCLC) , renal cancer  as well as head and neck cancer .
Additionally, a growing number of immunotherapeutics including peptide vaccines , dendritic cell vaccines , immunovirotherapy and cytokine therapy  are under clinical investigation for their safety and efficacy.
However, the response rates of many immunotherapy methods for glioma are low due to the special immune microenvironment of the CNS. To break the limitations of immunotherapy for glioma, researchers continue to make attempt The failure of the anti-tumor effect with single-agent or single-cell immunotherapy has prompted the multidisciplinary treatment of glioma and the optimal combination of all possible treatment methods. It is well known that macrophages are polarized into two subsets, M2 and M1. Among them, M1 macrophages secrete Th1 cytokines, such as IL-6, 8,12, and tumor necrosis factor (TNF)-α, leading to primarily anti-cancer responses. However, M2 macrophages produce Th2 cytokines such as IL-4, IL-10, and IL-13 to promote the proliferation of Th2 cells and induce immune tolerance by activation of Treg cells. Reducing recruitment of TAMs into the tumor microenvironment and fostering repolarization of M2 to M1 phenotype are being studied as new therapeutic strategies. Moreover, cytokine-based immunomodulators are being developed as adjuvant treatment approaches by correcting imbalanced immune function, improving immune suppression, and enhancing anti-tumor immune response .
IL10 is a pleiotropic cytokine mainly secreted by antigen-presenting cells such as activated T cells, B cells, monocytes, and macrophages, which can affect the activities of various cell types in the immune system. The immunomodulatory function of IL10 is mediated by the transmembrane signal transduction complex composed of IL10RA and IL10RB. Studies have shown that IL10 is associated with the survival, proliferation, and anti-apoptotic activity of various cancers such as Burkitt’s lymphoma , non-Hodgkin’s lymphoma , and non-small cell lung cancer . Targeting tumors with IL-10 not only prevents dendritic cell-mediated CD8 + T cell apoptosis, but also significantly improves antitumor effects in mice with advanced tumors when combined with immune checkpoint blockade (CmAb-(IL10)2) . Drugs related to IL10, such as IL10 fusion protein, polyethylene glycosylated IL10 (pegilodecakin) and adenovirus are in the clinical research stage, and initially demonstrated good anti-tumor effects . However, with the increasing research of IL-10 in tumor diseases, its role in the occurrence and development of different tumors has also been controversial. Especially, there are very few studies on IL10 and its signaling pathways in gliomas. Here, through a preliminary exploration of the database, we screened the close relationship between IL10RB and glioma, resulting in a comprehensive analysis of the expression, prognostic value, and function of IL10RB in glioma. According to our results, the high expression levels of IL10RB showed an association with the malignant phenotype, such as high WHO Grade, the IDH wildtype status, and mesenchymal subtype in gliomas. Critically, elevated IL10RB expression predicted significantly worse survival in glioma patients. We found that the high IL10RB expression was shown positively related to inflammatory activities and immune responses in whole gliomas, and glioma tissues with higher IL10RB expression are infiltrated with more microglia/macrophages. Further analysis indicated that IL10RB can promote the polarization of TAMs to protumoral M2 type. Meanwhile, we confirmed the strong correlation between IL10RB and some important immune checkpoints as PD-1, PD-L2, T cell immunoglobulin and mucin domain-3 (TIM-3), lymphocyte activation gene-3 (LAG3), indoleamine 2,3-dioxygenase 1 (IDO1), and inducible T cell costimulatory (ICOS). For these glioma patients, targeting IL10 and (or) IL10RB may be able to reduce immunosuppression through macrophage repolarization and synergistically enhance the therapeutic effect of immune checkpoint inhibitors.
Taken together, through the comprehensive bioinformatics analysis of IL10RB, we found that IL10RB was upregulated in high malignant glioma, and was an independent indicator for the clinical prognosis of glioma patients. Importantly, IL10RB was positively related to the infiltration of immune cells in the glioma microenvironment, especially TAMs and could predict the polarization of tumor-associated macrophages. These findings indicated IL10RB is a novel potential target for enhancing the anticancer therapies, and its value in clinical immunotherapy for glioma patients is worth a further study.
The limitations of this study are several. First, the public data source is a combination of multiple centers, the lack of partial data and the differences in data collection and treatment methods might directly lead to the deviation of analysis results.Secondly, performing the in vitro or/and in vivo experiments to verify our results would also make a difference.