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Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.

ABSTRACT: Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8+ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.

SUBMITTER: Guo X

PROVIDER: S-EPMC7195398 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Midkine activation of CD8<sup>+</sup> T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.

Guo Xiaofan X Pan Yuan Y Xiong Min M Sanapala Shilpa S Anastasaki Corina C Cobb Olivia O Dahiya Sonika S Gutmann David H DH

Nature communications 20200501 1

Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade gli ...[more]

PMID: 32358581

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Project description:Background: Chromosome 1p/19q codeletion is one of the most important genetic alterations for low grade gliomas (LGGs), and patients with 1p/19q codeletion have significantly prolonged survival compared to those without the codeletion. And the tumor immune microenvironment also plays a vital role in the tumor progression and prognosis. However, the effect of 1p/19q codeletion on the tumor immune microenvironment in LGGs is unclear. Methods: Immune cell infiltration of 281 LGGs from The Cancer Genome Atlas (TCGA) and 543 LGGs from the Chinese Glioma Genome Atlas (CGGA) were analyzed for immune cell infiltration through three bioinformatics tools: ESTIMATE algorithm, TIMER, and xCell. The infiltrating level of immune cells and expression of immune checkpoint genes were compared between different groups classified by 1p/19q codeletion and IDH (isocitrate dehydrogenase) mutation status. The differential biological processes and signaling pathways were evaluated through Gene Set Enrichment Analysis (GSEA). Correlations were analyzed using Spearman correlation. Results: 1p/19q codeletion was associated with immune-related biological processes in LGGs. The infiltrating level of multiple kinds of immune cells and expression of immune checkpoint genes were significantly lower in 1p/19q codeletion LGGs compared to 1p/19q non-codeletion cohorts. There are 127 immune-related genes on chromosome 1p or 19q, such as TGFB1, JAK1, and CSF1. The mRNA expression of these genes was positively correlated with their DNA copy number. These genes are distributed in multiple immune categories, such as chemokines/cytokines, TGF-β family members, and TNF family members, regulating immune cell infiltration and expression of the immune checkpoint genes in tumors. Conclusion: Our results indicated that 1p/19q codeletion status is closely associated with the immunosuppressive microenvironment in LGGs. LGGs with 1p/19q codeletion display less immune cell infiltration and lower expression of immune checkpoint genes than 1p/19q non-codeletion cases. Mechanistically, this may be, at least in part, due to the deletion of copy number of immune-related genes in LGGs with 1p/19q codeletion. Our findings may be relevant to investigate immune evasion in LGGs and contribute to the design of immunotherapeutic strategies for patients with LGGs.

Project description:BackgroundThe CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3) is differentially expressed in a variety of tumors and closely related to tumor occurrence and progression. The expression of CMTM3 was significantly elevated in glioma compared with normal brain tissue, to explore the potential function of CMTM3 in the prognosis and immune infiltration of glioma has certain clinical significance.MethodsThe tumor data in this study were derived from the sequencing data of various tumors in The Cancer Genome Atlas (TCGA) database. Low-grade glioma (LGG) data in the TCGA database include sequencing and clinical data. Clinical data mainly include survival time, survival outcome, age, WHO classification and other information. Sequencing data for normal tissues were obtained from the Genotype Tissue Expression (GTEx) database. Statistical analyses were mainly performed using bioinformatics tools and the corresponding R software (version 3.6.3). The Mann-Whitney U test (Wilcoxon rank sum test) was used to compare the expression differences between the tumor group and the normal group. Survival analysis was conducted using log-rank test to compare whether the overall survival (OS) time was statistically different between the CMTM3 high and low expression groups. The Tumor Immunity Estimation Resource (TIMER) database was used for immune infiltration analysis.ResultsThe results showed that the expression of CMTM3 in World Health Organization (WHO) II and WHO III gliomas was significantly higher than that of normal tissues (P<0.05). Glioma with high CMTM3 expression showed a lower overall survival (OS) (P<0.05). Gene enrichment analysis showed that CMTM3 was significantly enriched in 4 pathways (FDR <0.25, P<0.05). A high correlation was detected between CMTM3 and a variety of immune cells. CMTM3 is highly correlated with macrophages (r=0.536, P=1.31e-36), dendritic cells (r=0.546, P=2.85e-38), CD4+ T cells (r=0.517, P=6.17e-34).ConclusionsThe CMTM3 gene can be used as a potential prognostic marker for WHO grade II and WHO grade III glioma, is related to the immune infiltration in glioma microenvironment, and may became a new immunotherapy target.

Dataset Information

Midkine activation of CD8+ T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.

Publications

Midkine activation of CD8<sup>+</sup> T cells establishes a neuron-immune-cancer axis responsible for low-grade glioma growth.

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