Lower grade glioma (LGG) is a heterogeneous malignant brain tumor in humans that amounts to approximately 20% of intracranial tumors (Hoshide and Jandial, 2016). It was identified as grades II and III brain tumors by the World Health Organization. The incidence is estimated to be approximately 0.8 cases per 100,000 population (Nakasu and Nakasu, 2022). LGGs arise from supporting glial cells and usually affect young adults, and their main treatment involves surgical resection, followed by radiation and chemotherapy (Youssef and Miller, 2020). They are slowly growing tumors and often lack symptoms, except for seizures (Nakasu et al., 2021). While the pathogenesis mechanisms and risk factors for LGG are poorly understood, it seems plausible that an association of genetic susceptibility and biological, functional, and environmental factors influences the process (Darlix et al., 2017). The overall survival (OS) of LGG varies dramatically, as does the patient’s response to standard therapy (Brat and Pachter, 2015). For decades, there have been no significant improvements in the treatment of LGG; thus, the prognosis has not changed significantly (Claus et al., 2015).

Recently, immunotherapy has become an extremely promising strategy for many types of cancers and may help us improve the survival rate of patients with LGG. A dysfunctional immune response leads to tumor immune evasion in gliomas (Wang et al., 2018). Immunotherapy can block the dysfunction and kill cancer cells by activating the immune system (Chuah and Chew, 2020). Currently, immune checkpoint inhibitors (ICIs) are the most successful immunotherapy drugs in use, while programmed death-ligand 1 (PD-L1) expression, microsatellite instability, mismatch repair, and tumor mutation burden (TMB) are the most valuable biomarkers for predicting ICI efficiency (Hodges et al., 2017; Rizvi et al., 2018). Yin et al. (2020) found that TMB is negatively related to immune infiltration and OS in LGG. However, unlike other prevalent solid malignant tumors, the immune activity and immunotherapy efficiency are still largely unknown in LGG and need to be studied further.

ATP binding cassette subfamily C member 8 (ABCC8), an ATP-binding cassette (ABC) transporter, leads to multidrug resistance in many kinds of cancer cells by pumping anticancer agents out. ABCC8 variant was linked with diabetes and hypertension by numerous studies (Beltrand et al., 2020; de Franco et al., 2020; Flagg et al., 2007; Southgate et al., 2020). Recently, Rehman et al. (2022, 2020) also reported that the genetic variant of ABCC8 is associated with cardiac diseases and metabolic disorders. Loss-of-function mutations of ABCC8 were also reported by Bohnen et al. (2018) to be associated with pulmonary arterial hypertension (Bohnen et al., 2018). Its expression was found to promote cerebral edema after brain ischemia and injury (Alquisiras-Burgos et al., 2020). The expression of ABCC8 was also decreased in pancreatic, lung, and breast cancers. Interestingly, in these tumors, ABCC8 expression was linked to favorable survival (Hlavac et al., 2013; Mohelnikova-Duchonova et al., 2013; Wang et al., 2020). A recent study reported that ABCC8 mRNA levels are positively related to survival in patients with glioma (Zhou et al., 2020). ABC transporters regulate the development, differentiation, and maturation of immune cells and are involved in the migration of immune effector cells to sites of inflammation (van de Ven et al., 2009). They were also shown recently to regulate T-cell populations, such as thymocytes, natural killer T cells, CD8+ T cells, and regulatory T cells (Thurm et al., 2021). One family member, ABCC5, was shown by Chen et al. (2021) to be associated with immune infiltration of hepatocellular carcinoma. However, whether ABCC8 participates in immune responses and provides survival benefits in LGG is still not clear and needs to be investigated.

In this study, we systematically evaluated whether ABCC8 expression reflects the immune microenvironment of LGG tumor tissues. The results were verified in several independent datasets. We also attempted to identify the related signaling pathways. The association between ABCC8 gene expression and LGG patient survival was also investigated. This study might help identify an ideal biomarker for predicting survival and sensitivity to immunotherapy in patients with LGG.

ABCC8 encodes ATP binding cassette subfamily C member 8, also known as sulfonylurea receptor 1 (SUR1). It belongs to the ATP binding cassette transporter superfamily, which regulates multidrug resistance of cells by transporting various molecules across extra and intracellular membranes. Numerous studies have indicated the association between ABCC8 and diabetes, hypertension, cardiac diseases, and metabolic disorders (Rehman et al., 2022; Rehman et al., 2020). In the nerve system, ABCC8 has been found to control the activity of ATP-sensitive potassium channels (Martin et al., 2020). These channels are widely expressed in all cells of the neurovascular unit and induce the efflux of potassium to decrease neuronal excitability (Yamada and Inagaki, 2005; Zhang et al., 2018). ATP-sensitive potassium channels could also affect neurotransmitter release by the process mentioned above.

In general, ABCC8 was found to participate in the inflammatory process, resulting in cytotoxic edema and cell apoptosis in many neurological diseases, including ischemic stroke, spinal cord injury, subarachnoid hemorrhage, traumatic brain injury, and brain metastasis (Simard et al., 2006; Simard et al., 2009a; Simard et al., 2009b; Simard et al., 2007; Thompson et al., 2013). Glibenclamide, an ABCC8 inhibitor, was found to improve neurological functions and reduce mortality in patients with diabetic acute ischemic stroke (Gladstone et al., 2009; Kunte et al., 2012). Thompson et al. (2013) also reported that glibenclamide could reduce brain edema in a mouse model of brain metastasis (Thompson et al., 2013).

The putative role of ABCC8 in brain tumors has been shown earlier. Thompson et al. (2018) reported a higher expression of ABCC8 in medulloblastoma and supratentorial ependymoma than in glioblastoma, which suggests that the expression of ABCC8 is higher in benign brain tumors than in malignant tumors (Thompson et al., 2018). Recently, Zhou et al. (2020) found that ABCC8 expression levels are negatively related to the World Health Organization grade, 1p/19q noncodeletion, and IDH wild type in gliomas, while patients with high ABCC8 mRNA expression showed a longer survival period than others. However, the underlying mechanism has not been illustrated.

Our study found a significantly lowered ABCC8 mRNA expression in LGG than in normal tissues and was positively correlated with a favorable prognosis in LGG, consistent with previous studies. We also observed a negative correlation between ABCC8 mRNA expression and B cells, macrophages, neutrophils, and dendritic cells in LGG, which has not been discussed thus far. Varied ABCC8 gene copy numbers also seem to reflect different immune cell infiltration levels; however, owing to the relatively small mutation numbers, the results should be validated by a mouse model in vivo. ABCC8 expression was also found to be negatively correlated with markers of Treg and T-cell failure (PDCD1, CD274, CTLA4, LAG3, and HAVCR2/TIM3) and TMB, which may indicate that LGG patients without ABCC8 expression should have a good response to immune therapy. GSEA demonstrated a negative association between the expression of ABCC8 and the B-cell receptor signaling pathway, antigen processing and presentation pathway, FC gamma-mediated phagocytosis pathway, and leukocyte transendothelial migration pathway. Interestingly, these immune pathways matched only the B cells, macrophages, neutrophils, and dendritic cells that we found were related to ABCC8 expression. KEGG pathway analysis of ABCC8-related genes through TCGA_LGG data revealed that the GABAergic synapse signaling pathway is involved in the ABCC8-mediated immune response. Collectively, these findings imply that ABCC8 plays an important role in recruiting and governing non-T immune cells in LGG and may influence survival by regulating the antitumor immune response. To our knowledge, this is the first study to report a link between ABCC8 and tumor immunity in LGG.

There have been limited studies on the relationship between ABCC8 and immunity, with a focus on brain diseases. Thompson et al. (2018) reported that ABCC8 is a putative therapeutic target to reduce neuroinflammation in adult and pediatric brain tumors. Makar et al. (2015) found that silencing or inhibiting ABCC8 leads to a reduced inflammatory burden and correlates with better preservation of myelin, better preservation of axons, and more numerous mature and precursor oligodendrocytes in mouse models (Makar et al., 2015). In murine experimental autoimmune encephalomyelitis models, blockage of ABCC8-TRPM4 channels, expressed mostly by astrocytes, dramatically decreased the inflammatory response by downregulating TNF, BAFF, CCL2, and NOS2 mRNA (Gerzanich et al., 2017). Astrocytes only exist in the central neuron system, which may explain the results of our study. Regarding the studies focusing on ABCC8 and cancer immunity, there was only one study by Meng et al. (2022) was found on the PubMed website, which reported a positive correlation of ABCC8 with CD4+ T-cell and macrophage infiltration and a negative correlation with OS in liver hepatocellular carcinoma, totally opposite to our results, probably due to the different tumor backgrounds.

Recently, immunotherapy has revolutionized many kinds of solid malignant tumor treatments. Although its efficiency rate is not very high, it could bring great survival benefits to the responsive population. A major problem is finding the correct population. Luckily, ICIs have been proven to penetrate the blood-brain barrier and thus could be a promising immunotherapy strategy for LGG. Previous studies with glioma mouse models have proven that the inhibition of CTLA-4, IDO, or PD-L1 could significantly reduce tumor-infiltrating Treg cell numbers and increase survival, which indicates that ICIs may have wide application prospects in glioma treatment in the future (Wainwright et al., 2014). To date, some related clinical trials have indicated limited efficacy of ICIs, although most trials have not yet been completed (Xu et al., 2020). The mechanism underlying this paradox has not been illustrated. Our results showed that the TMB of LGG is quite low, so the anticancer immune response is probably inhibited because of a lack of antigen stimulation, which may partly explain the problem. Since the OS of LGG ranges from 1 to 15 years due to its large intrinsic biological and clinical heterogeneity, the detailed classification of LGG may help improve the efficiency of immunotherapy. Based on our present study, we found that ABCC8 may be a promising biomarker to predict the ICI treatment response.

We must acknowledge that there are several potential limitations in the present analysis. The study was a retrospective analysis, and all analyses were carried out based on public datasets. The results need to be validated in large, prospective studies. In addition, the mechanisms underpinning ABCC8-mediated antitumor immunity have not been fully illustrated. The GABAergic synapse signaling pathway, which has been proven to play a crucial role in immune cell immunomodulation by many studies, may be responsible for the phenomenon (Jin et al., 2013; Kim et al., 2018; Zheng et al., 2021). Finally, the average anticancer immune response is probably low in LGG, and whether modulators of ABCC8 or the GABAergic synapse signaling pathway can stimulate the immune response to provide survival benefits to LGG patients receiving ICIs remains to be elucidated. Subsequent experimental verification is required to test this hypothesis.

The results of this study suggest that ABCC8 might play a crucial role in regulating LGG tumor immunity. The mRNA expression levels of ABCC8 were independently predictive of OS in LGG, which indicated that ABCC8 could be a candidate biomarker for favorable survival. Non-T immune cells and the GABAergic synapse signaling pathway may participate in ABCC8-associated immune regulation. The potential role of ABCC8 inhibitors, such as glibenclamide, in interfering with immune cells should be evaluated. Whether a combination of ABCC8 inhibitors and ICIs could provide more survival benefits for LGG patients also needs to be discussed.