The Non-N(6)-Methyladenosine Epitranscriptome Patterns and Characteristics of Tumor Microenvironment Infiltration and Mesenchymal Transition in Glioblastoma.

An increasing number of RNA modification types other than N6-methyladenosine (m6A) modification have been detected. Nonetheless, the probable functions of RNA modifications beyond m6A in the tumor microenvironment (TME), mesenchymal (MES) transition, immunotherapy, and drug sensitivity remain unclear. We analyzed the characteristics of 32 non-m6A RNA modification regulators in 539 glioblastoma (GBM) patients and the TME cell infiltration and MES transition patterns. Using principal component analysis, a non-m6A epitranscriptome regulator score (RM score) model was established. We estimated the association between RM score and clinical characteristics, TME status, GBM subtypes, and drug and immunotherapy response. Three definite non-m6A RNA modification patterns associated with diverse biological pathways and clinical characteristics were identified. The high RM score group was characterized by a poor prognosis, enhanced immune infiltration, and MES subtype. Further analysis indicated that the high RM score group had a lower tumor mutation burden as well as a weaker response to immunotherapy. The higher RM score group may benefit more from drugs targeting the EGFR and WNT signaling pathways. Our study exposed the potential relationship of non-m6A RNA modification regulators with clinical features, TME status, and GBM subtype and clarified its therapeutic value.

Xu J ，Gao Z ，Liu K ，Fan Y ，Zhang Z ，Xue H ，Guo X ，Zhang P ，Deng L ，Wang S ，Wang H ，Wang Q ，Zhao R ，Li G ... -  《Frontiers in Immunology》

Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer.

Chen H ，Yao J ，Bao R ，Dong Y ，Zhang T ，Du Y ，Wang G ，Ni D ，Xun Z ，Niu X ，Ye Y ，Li HB ... -  《Molecular Cancer》

The N(6)-Methyladenosine-Modified Pseudogene HSPA7 Correlates With the Tumor Microenvironment and Predicts the Response to Immune Checkpoint Therapy in Glioblastoma.

Glioblastoma (GBM), one of the most aggressive tumors of the brain, has no effective or sufficient therapies. Identifying robust biomarkers for the response to immune checkpoint blockade (ICB) therapy, a promising treatment option for GBM patients, is urgently needed. We comprehensively evaluated lncRNA m6A modification patterns in m6A-sequencing (m6A-seq) data for GBM tissues and systematically investigated the immune and stromal regulators of these m6A-regulated lncRNAs. We used the single-sample gene-set enrichment analysis (ssGSEA) algorithm to investigate the difference in enriched tumor microenvironment (TME) infiltrating cells and the functional annotation of HSPA7 in individual GBM samples. Further, we validated that HSPA7 promoted the recruitment of macrophages into GBM TME in vitro, as well as in our GBM tissue section. We also explored its impact on the efficacy of ICB therapy using the patient-derived glioblastoma organoid (GBO) model. Here, we depicted the first transcriptome-wide m6A methylation profile of lncRNAs in GBM, revealing highly distinct lncRNA m6A modification patterns compared to those in normal brain tissues. We identified the m6A-modified pseudogene HSPA7 as a novel prognostic risk factor in GBM patients, with crucial roles in immunophenotype determination, stromal activation, and carcinogenic pathway activation. We confirmed that HSPA7 promoted macrophage infiltration and SPP1 expression via upregulating the YAP1 and LOX expression of glioblastoma stem cells (GSCs) in vitro and in our clinical GBM tumor samples. We also confirmed that knockdown of HSPA7 might increase the efficiency of anti-PD1 therapy utilizing the GBO model, highlighting its potential as a novel target for immunotherapy. Our results indicated that HSPA7 could be a novel immunotherapy target for GBM patients.

Zhao R ，Li B ，Zhang S ，He Z ，Pan Z ，Guo Q ，Qiu W ，Qi Y ，Zhao S ，Wang S ，Chen Z ，Zhang P ，Guo X ，Xue H ，Li G ... -  《Frontiers in Immunology》

m(6)A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer.

Zhang B ，Wu Q ，Li B ，Wang D ，Wang L ，Zhou YL ... -  《Molecular Cancer》

N6-Methyladenosine Regulator-Mediated Immue Patterns and Tumor Microenvironment Infiltration Characterization in Glioblastoma.

Epigenetic modifications, according to emerging evidence, perform a critical role for cellular immune response and tumorigenesis. Nonetheless, the role of N6-methyladenosine modification in shaping of the glioblastoma tumor microenvironment is unknown. N6-methyladenosine(m6A) methylation patterns in GBM patients were evaluated via multiple omics analysis of 15 m6A regulators and systematically correlated with tumor immune features. For quantification of N6-methyladenosine methylation patterns of individual patients, GM-score was developed and correlated with clinical and immunological characteristics. Glioblastoma has two different m6A methylation patterns that are strongly associated with TME characteristics, tumor subtype, immunotherapy response, and patient prognosis. High-GM-score is associated with an immune tolerance phenotype dominated by the IDH1 wild molecular subtype and the Mesenchymal tissue subtype, as well as a high infiltration of immune cells and stromal cells and a poor prognosis. Furthermore, despite higher immune checkpoint expression, individuals with a high-GM-score have a poorer response to anti-CTLA4 immunotherapy regimens due to T-cells dysfunctional. Low-GM-score individuals had an immunodeficient phenotype dominated by IDH mutant molecular subtypes and Proneural tissue subtypes, with less immune cell infiltration and a better prognosis. Furthermore, patients with low-GM-scores had higher microsatellite instability (MSI) and t-cell exclusion scores, as well as a better response to anti-CTLA4 immunotherapy regimens. This study demonstrated that m6A modification patterns play an important role in the shaping of TME complexity and diversity. The GM-score could identify m6A modification patterns in individual patients, resulting in a more personalization and efficacious anti-tumor immunotherapy strategy.

Xiong W ，Li C ，Wan B ，Zheng Z ，Zhang Y ，Wang S ，Fan J ... -  《Frontiers in Immunology》