GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment.

Publication date: Dec 13, 2019

General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor-binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma. We found that myeloid-lineage deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) that promotes antitumor immunity. Time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing showed that this was due to changes in the immune microenvironment with increased proinflammatory activation of macrophages and MDSCs and interferon-? expression in intratumoral CD8 T cells. Mechanistically, GCN2 altered myeloid function by promoting increased translation of the transcription factor CREB-2/ATF4, which was required for maturation and polarization of macrophages and MDSCs in both mice and humans, whereas targeting Atf4 by small interfering RNA knockdown reduced tumor growth. Last, analysis of patients with cutaneous melanoma showed that GCN2-dependent transcriptional signatures correlated with macrophage polarization, T cell infiltrates, and overall survival. Thus, these data reveal a previously unknown dependence of tumors on myeloid GCN2 signals for protection from immune attack.

Halaby, M.J., Hezaveh, K., Lamorte, S., Ciudad, M.T., Kloetgen, A., MacLeod, B.L., Guo, M., Chakravarthy, A., Medina, T.D.S., Ugel, S., Tsirigos, A., , Bronte, Munn, D.H., Pugh, T.J., De Carvalho, D.D., Butler, M.O., Ohashi, P.S., Brooks, D.G., and McGaha, T.L. GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment. 25140. 2019 Sci Immunol (4):42.

Concepts Keywords
CD8 Last cutaneous melanoma
CREB Immune tumors
Immunity Dependence tumors
Immunosuppression Immunosuppression
Interferon Branches of biology
Macrophage Cell biology
Macrophages Immune system
Melanoma Macrophages
Microenvironment Tumor
Myeloid Tumor microenvironment
Nutrient Gcn2
Oncology Macrophage polarization
Phenotype Myeloid-derived suppressor cell
Polarization Transcriptomics
Sci
Sensor
Suppressor
Time
Transcription
Transcription Factor
Transcriptomics
Tumor

Semantics

Type Source Name
disease MESH tumor
pathway REACTOME Translation
disease MESH melanoma
pathway KEGG Melanoma
disease MESH growth

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