Journal
FRONTIERS IN IMMUNOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.653711
Keywords
N-6-methyladenosine; tumor microenvironment; glioblastoma; immune checkpoint blockade; HSPA7
Categories
Funding
- National Natural Science Foundation of China [81874083, 82072776, 82072775, 81702468, 81802966, 81902540, 81874082, 81472353]
- Natural Science Foundation of Shandong Province of China [ZR2019BH057, ZR2020QH174]
- Key clinical Research project of Clinical Research Center of Shandong University [2020SDUCRCA011]
- Taishan Pandeng Scholar Program of Shandong Province [tspd20210322]
Ask authors/readers for more resources
By studying the lncRNA m(6)A modification patterns in GBM tissues, we identified HSPA7 as a novel prognostic risk factor in GBM patients, playing important roles in immunophenotype and tumor microenvironment. We also confirmed the impact of HSPA7 on macrophage infiltration and the efficacy of ICB therapy.
Background: 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. Methods: We comprehensively evaluated lncRNA m(6)A modification patterns in m(6)A-sequencing (m(6)A-seq) data for GBM tissues and systematically investigated the immune and stromal regulators of these m(6)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 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. Results: Here, we depicted the first transcriptome-wide m(6)A methylation profile of lncRNAs in GBM, revealing highly distinct lncRNA m(6)A modification patterns compared to those in normal brain tissues. We identified the m(6)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 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. Conclusions: Our results indicated that HSPA7 could be a novel immunotherapy target for GBM patients.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available