Gliomas are a group of tumors with widely varying prognoses, and their accurate diagnosis and effective treatment remain a challenge[1, 3]. Here, we have developed the IFNGR score to characterize the prognosis of gliomas based on the expression of IFNGR1 and IFNGR2, two receptors necessary for IFNG signaling. As expected, the IFNGR score well represents the IFNG-related biological processes and extensively correlates with clinicopathological parameters that indicate a poor prognosis of glioma. Besides, we found that the IFNGR score was a robust biomarker of OS and PFI, and had the potential to screen ICB responders. Together, our work provides valuable information for the diagnosis, prognosis, and classification of gliomas and may help to optimize immunotherapy.
To our knowledge, we have for the first time explored the role of IFNGR1 and IFNGR2 in glioma. IFNGR1 and IFNGR2 comprise the heterodimeric receptor for IFNG and their dysfunction is involved in various pathologies. One clinical study contains 213 patients and 733 controls has shown a correlation between IFNGR1 -56C/T polymorphism and early onset of gastric carcinoma. A possible explanation is that individuals carrying the IFNGR1 -56*T allele produce more IFNGR1, which renders cells more sensitive to IFNG, resulting in a more pro-inflammatory microenvironment upon H pylori infection. Besides, loss of tumor-suppressive transcription factor Elf5 promotes the growth and metastasis of triple-negative breast cancer through stabilizing IFNGR1. On the other hand, the IFNGR2 is involved in the regulation of Th1 and Th17 homeostasis, and the lack of which is associated with mycobacterial disease[11, 12]. In line with these findings, we found that the IFNGR score was positively correlated with the malignant biomarkers of gliomas in terms of histology, WHO grade, and transcriptome subtype. Interestingly, GO analysis corroborates the proinflammatory microenvironment of the IFNGR score-high group, suggesting that the upregulation of IFNGR1 and IFNGR2 was associated with enhanced inflammatory and immune response in gliomas. Nevertheless, an active immune response does not necessarily benefit glioma patients. For instance, the immune cytolytic activity measuring the function of CD8+ T cell, and the IFNG response genes indicating activation of adaptive immune responses were negatively correlated with the overall survival of glioma patients[6, 22], which is in line with our findings. Therefore, manipulation of the immune response for long-term control of glioma growth requires a deeper understanding of the composition of the immune response and the specific tumor microenvironment of gliomas.
IFNG is a double-edged sword immune-modulator and its role in glioma remains controversial. On the one hand, IFNG involves in the differentiation of Th1 cells, maintains the Th1-type immune response, as well as enhances the cytotoxicity of T lymphocytes, making the IFNG gene signatures effective biomarkers of an activated anti-tumor immune response[7, 23–25]. Nevertheless, studies revealed that IFNG promotes tumor immune evasion by upregulating PD-L1 in a JAK-STAT pathway-dependent manner, implying that tumors characterized by increased IFNG response may be sensitive to immune checkpoint blockade therapy[5–7, 26]. Given that IFNGR1 and IFNGR2 are receptors indispensable in the IFNG-mediated activation of the JAK and STAT families[4, 8], it was plausible that the 2-gene signature characterizes the upregulation of the IFNG signaling pathway well, and that patients in the IFNGR score-high group were potential responders to ICB therapy. However, multiple mechanisms are involved in the formation of glioma immunosuppressive microenvironment. For example, TGF-beta is involved in the inhibition of antigen presentation, the function of antigen-presenting cells, and the activation of T cells, COX-2 and PGE2 participate in tumor growth and angiogenesis, as well as CCL2, recruits immunosuppressive cells such as regulatory T cells and MDSC[29, 30]. Therefore, it is necessary to take into account the role of other immunosuppressive mechanisms while applying ICB in the treatment of gliomas.