Research ArticleTUMOR IMMUNITY

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

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Science Immunology  13 Dec 2019:
Vol. 4, Issue 42, eaax8189
DOI: 10.1126/sciimmunol.aax8189

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Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) suppress T cell functions in the tumor microenvironment (TME). Halaby et al. examine how the serine-threonine kinase general control nonderepressible 2 (GCN2) is a critical driver of Mϕ and MDSC polarization in the TME. Myeloid-lineage deletion of GCN2 caused a shift in TAM and MDSC phenotypes toward increased antitumor responses within the TME due to proinflammatory responses and increased CD8+ T cell expression of IFN-γ. GCN2 was a critical driver of Mϕ polarization and immunosuppression within the TME by promoting translation of the CREB-2/ATF4 transcription factor. GCN2 activity negatively correlated with antitumor responses and overall survival in human melanoma, suggesting further study into therapeutic targeting of this gene.

Abstract

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-γ 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.

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