Identification of a unique tumor cell subset employing myeloid transcriptional circuits to create an immunomodulatory microenvironment in glioblastoma. (31st December 2022)

• Record Type: Journal Article
• Authors: Yang, Kaidi; Shi, Yu; Luo, Min; Mao, Min; Zhang, Xiaoning; Chen, Cong; Liu, Yuqi; He, Zhicheng; Liu, Qing; Wang, Wenying; Luo, Chunhua; Yin, Wen; Wang, Chao; Niu, Qin; Zeng, Hui; Bian, Xiu-Wu; Ping, Yi-Fang
• Is Part Of: Oncoimmunology. Volume 11:Number 1(2022)
• Publication Date: 2022-12-31
• Subjects: glioblastoma -- molecular subtyping -- single-cell RNA sequencing -- prognosis; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2022.2030020
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Glioblastoma (GBM) is an aggressive primary brain tumor with unique immunity predominated by myeloid cells. GBM cells have been implicated to evade immune attack through hijacking myeloid-affiliated transcriptional programs to establish an immunosuppressive microenvironment. However, molecular features of immune-evading GBM cells in heterogeneous GBMs and their interactions with immune cells remain unclear. Herein, we employed single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data to develop an in silico method for delineating GBM immune signature and identifying new molecular subsets for immunotherapy. We identified a new GBM cell subset, termed TC-6, that harbored immune-invading signature and actively interacted with tumor-associated macrophages (TAMs) to orchestrate an immune-suppressive niche. Proinflammatory transcriptional factors STAT1, STAT2, IRF1, IRF2, IRF3, and IRF7 were identified as the core regulons defining TC-6 subsets. Further immune transcriptome analyses revealed three immune subtypes (C1, C2, and C3). C3 subtype GBMs were enriched with TC-6 cells and immunosuppressive TAMs, and exhibited an immunomodulatory signature that associated with reduced efficacy of anti-PD-1 treatment. Interferon-related DNA damage resistance signaling was upregulated in C3 GBMs, predicting shortened survival of GBM patients who received chemo-radiation treatment. Treatment of OSI-930 as a molecular agent targeting c-kit and VEGFR2 tyrosine kinases may compromise the immunomodulatory signature of C3 GBMs and synergize with chemo-radiation therapy. We further developed a simplified 11-gene set for defining C3 GBMs. Our work identified TC-6 subset as an immune-evading hub that creates an immunomodulatory signature of C3 GBMs, gaining insights into the heterogeneity of GBM immune microenvironment and holding promise for optimized anti-GBM immunotherapy.