FGL2 promotes tumor progression in the CNS by suppressing CD103+ dendritic cell differentiation

• Published in: Nature communications Vol. 10; no. 1; pp. 448 - 15
• Main Authors: Yan, Jun, Zhao, Qingnan, Gabrusiewicz, Konrad, Kong, Ling-Yuan, Xia, Xueqing, Wang, Jian, Ott, Martina, Xu, Jingda, Davis, R. Eric, Huo, Longfei, Rao, Ganesh, Sun, Shao-Cong, Watowich, Stephanie S., Heimberger, Amy B., Li, Shulin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/31; 13/51; 14/19; 45/23; 631/67; 631/67/1922; 631/67/580; 64/60; Animals; Antigens, CD - genetics; Antigens, CD - immunology; Arbitration; Brain; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - immunology; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain tumors; CD103 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell activation; Cell Differentiation; Cell Line, Tumor; Cell proliferation; Cerebrospinal fluid; Colony-stimulating factor; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; Differentiation (biology); Disease Progression; Fgl2 protein; Fibrinogen; Fibrinogen - genetics; Fibrinogen - immunology; Gene expression; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - genetics; Glioblastoma - immunology; Glioblastoma - mortality; Glioblastoma - pathology; Glioma; Glioma cells; Granulocyte-macrophage colony stimulating factor; Heterografts; Humanities and Social Sciences; Humans; Immunodeficiency; Immunoregulation; Integrin alpha Chains - genetics; Integrin alpha Chains - immunology; Kinases; Lymph nodes; Mice; Mice, Transgenic; multidisciplinary; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - pathology; Neuroglia - immunology; Neuroglia - pathology; NF-kappa B - genetics; NF-kappa B - immunology; NF-κB protein; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - immunology; Proteins; Science; Science (multidisciplinary); STAT Transcription Factors - genetics; STAT Transcription Factors - immunology; Stat1 protein; Stem cell transplantation; Stem cells; Survival Analysis; Tumor Burden; Tumor cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-08271-x

Few studies implicate immunoregulatory gene expression in tumor cells in arbitrating brain tumor progression. Here we show that fibrinogen-like protein 2 (FGL2) is highly expressed in glioma stem cells and primary glioblastoma (GBM) cells. FGL2 knockout in tumor cells did not affect tumor-cell proliferation in vitro or tumor progression in immunodeficient mice but completely impaired GBM progression in immune-competent mice. This impairment was reversed in mice with a defect in dendritic cells (DCs) or CD103 + DC differentiation in the brain and in tumor-draining lymph nodes. The presence of FGL2 in tumor cells inhibited granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CD103 + DC differentiation by suppressing NF-κB, STAT1/5, and p38 activation. These findings are relevant to GBM patients because a low level of FGL2 expression with concurrent high GM-CSF expression is associated with higher CD8B expression and longer survival. These data provide a rationale for therapeutic inhibition of FGL2 in brain tumors. Fibrinogen-like protein 2 (FGL2) mediates immune suppression in glioblastoma (GBM). Here, the authors show that FGL-2 expressed by GBM cancer cells acts by suppressing the differentiation of CD103+ DC cells required to activate the anti-tumor CD8+ T cell response via blocking GM-CSF signalling at NFKB, STAT1/5 and p38 level.