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

Marie Jo Halaby, Kebria Hezaveh, Sara Lamorte, M. Teresa Ciudad, Andreas Kloetgen, Bethany L. MacLeod, Mengdi Guo, Ankur Chakravarthy, Tiago Da Silva Medina, Stefano Ugel, Aristotelis Tsirigos, Vincenzo Bronte, David H. Munn, Trevor J. Pugh, Daniel D. De Carvalho, Marcus O. Butler, Pamela S. Ohashi, David G. Brooks, Tracy L. McGaha

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2 Scopus citations

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.

Original languageEnglish (US)
JournalScience immunology
Volume4
Issue number42
DOIs
StatePublished - Dec 13 2019

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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, V., Munn, D. H., Pugh, T. J., De Carvalho, D. D., Butler, M. O., Ohashi, P. S., Brooks, D. G., & McGaha, T. L. (2019). GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment. Science immunology, 4(42). https://doi.org/10.1126/sciimmunol.aax8189