Distinct immune escape and microenvironment between RG-like and pri-OPC-like glioma revealed by single-cell RNA-seq analysis

Abstract

The association of neurogenesis and gliogenesis with glioma remains unclear. By conducting single-cell RNA-seq analyses on 26 gliomas, we reported their classification into primitive oligodendrocyte precursor cell (pri-OPC)-like and radial glia (RG)-like tumors and validated it in a public cohort and TCGA glioma. The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations, and the pri-OPC-like ones were prone to carrying TP53 mutations. Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes, suggesting their distinct immune evasion programs. Furthermore, the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners. Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes. For example, glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes, respectively. Their expression was positively correlated with those of immune checkpoint genes (e.g., LGALS3) and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells. This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.

Keywords

single-cell RNA-seq / glioma / radial glia / primitive oligodendrocyte precursor cell / immune escape

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Acknowledgements

We thank Melanie Hayden Gephart and Gong-Hong Wei for their help in providing critical comments on the manuscript. Linya You was supported by talent startup funding from Fudan University (Nos. JIF101017, SXF101012, and JIF101047) and Science Innovation 2030—Brain Science and Brain-Inspired Intelligence Technology Major Project (No. 2021ZD0201100 Task 4 and No. 2021ZD0201104) from the Ministry of Science and Technology (MOST), China. Jinsong Wu was supported by Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01) and ZJ Lab, and operating grant of Shanghai Brain Bank technical system (No. 16JC1420103). Edwin Wang was supported by Alberta Innovates Translational Chair Program in Cancer Genomics, the Natural Sciences and Engineering Research Council of Canada (NSERC, No. RGPIN-2017-04885), and Canadian Foundation of Innovation (No. 36655).

Compliance with ethics guidelines

Conflicts of interest Weiwei Xian, Mohammad Asad, Shuai Wu, Zhixin Bai, Fengjiao Li, Junfeng Lu, Gaoyu Zu, Erin Brintnell, Hong Chen, Ying Mao, Guomin Zhou, Bo Liao, Jinsong Wu, Edwin Wang, and Linya You declare that they have no conflict of interest.

The study was approved by the Ethics Committee of Huashan Hospital Affiliated to Fudan University (IRB# 2018-220) and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients included in the study.

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