Tumor Immune Microenvironment Landscape in Glioma Identifies a Prognostic and Immunotherapeutic Signature.

Chunyu Zhang,Na Luo,Pengfei Xu,Qianxue Chen,Liguo Ye,Daofeng Tian,Zhongzhou Su,Xiaobin Li,Yinqiu Tan,Lirui Guo,Shiao Tong,Haitao Liu

doi:10.3389/fcell.2021.717601

Abstract

The tumor immune microenvironment (TIME) has been recognized to be associated with sensitivity to immunotherapy and patient prognosis. Recent research demonstrates that assessing the TIME patterns on large-scale samples will expand insights into TIME and will provide guidance to formulate immunotherapy strategies for tumors. However, until now, thorough research has not yet been reported on the immune infiltration landscape of glioma. Herein, the CIBERSORT algorithm was used to unveil the TIME landscape of 1,975 glioma observations. Three TIME subtypes were established, and the TIMEscore was calculated by least absolute shrinkage and selection operator (LASSO)–Cox analysis. The high TIMEscore was distinguished by an elevated tumor mutation burden (TMB) and activation of immune-related biological process, such as IL6-JAK-STAT3 signaling and interferon gamma (IFN-γ) response, which may demonstrate that the patients with high TIMEscore were more sensitive to immunotherapy. Multivariate analysis revealed that the TIMEscore could strongly and independently predict the prognosis of gliomas [Chinese Glioma Genome Atlas (CGGA) cohort: hazard ratio (HR): 2.134, p < 0.001; Gravendeel cohort: HR: 1.872, p < 0.001; Kamoun cohort: HR: 1.705, p < 0.001; The Cancer Genome Atlas (TCGA) cohort: HR: 2.033, p < 0.001; the combined cohort: HR: 1.626, p < 0.001], and survival advantage was evident among those who received chemotherapy. Finally, we validated the performance of the signature in human tissues from Wuhan University (WHU) dataset (HR: 15.090, p = 0.008). Our research suggested that the TIMEscore could be applied as an effective predictor for adjuvant therapy and prognosis assessment.

Highlights

Glioma is one of the most common malignancies in the world, with high morbidity and mortality owing to their localization and often locally invasive growth (Siegel et al, 2019)
We performed the CIBERSORT to quantify the fractions of 22 immune cells in glioma samples (Supplementary Table 3)
tumor immune microenvironment (TIME) cluster A was identified to be related to an advantageous outcome with a median survival up to 697 days, which was characterized by high infiltrations of M1 macrophages, plasma cells activated CD4 + T memory cells, T follicular helper (Tfh) cells, activated NK cells, activated mast cells, and naive B cells, while there is a lack of infiltrations of CD8 + T cells and activated dendritic cells

Summary

Introduction

Glioma is one of the most common malignancies in the world, with high morbidity and mortality owing to their localization and often locally invasive growth (Siegel et al, 2019) It remains the tumor with the highest incidence in the central nervous system (CNS), accounting for about 25% of primary intracranial neoplastic lesions (Weller et al, 2015; Louis et al, 2016). With the development of research, there are remarkable achievements in exploring the molecular pathogenesis of gliomas, such as the isocitrate dehydrogenase (IDH) status and O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation. These findings accelerate the improvement of diagnostics, classification systems, and precision therapy. Further investigations are essential into identification of new molecular targets, tools for prognostic assessment, and development of therapeutic regimens that provide the potentiality for improved events in the near future

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Results

Conclusion