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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Polarization Player

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.

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