AUTHOR=Zhao Rongrong , Li Boyan , Zhang Shouji , He Zheng , Pan Ziwen , Guo Qindong , Qiu Wei , Qi Yanhua , Zhao Shulin , Wang Shaobo , Chen Zihang , Zhang Ping , Guo Xing , Xue Hao , Li Gang 

TITLE=The N6-Methyladenosine-Modified Pseudogene HSPA7 Correlates With the Tumor Microenvironment and Predicts the Response to Immune Checkpoint Therapy in Glioblastoma

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.653711

DOI=10.3389/fimmu.2021.653711

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>We comprehensively evaluated lncRNA m<sup>6</sup>A modification patterns in m<sup>6</sup>A-sequencing (m<sup>6</sup>A-seq) data for GBM tissues and systematically investigated the immune and stromal regulators of these m<sup>6</sup>A-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 <italic>in vitro</italic>, 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.</p></sec><sec><title>Results</title><p>Here, we depicted the first transcriptome-wide m<sup>6</sup>A methylation profile of lncRNAs in GBM, revealing highly distinct lncRNA m<sup>6</sup>A modification patterns compared to those in normal brain tissues. We identified the m<sup>6</sup>A-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 <italic>via</italic> upregulating the YAP1 and LOX expression of glioblastoma stem cells (GSCs) <italic>in vitro</italic> 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.</p></sec><sec><title>Conclusions</title><p>Our results indicated that HSPA7 could be a novel immunotherapy target for GBM patients.</p></sec>