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

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.

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

“…Evidence points to conflicting effects of IL-1β with respect to the TIME. While some studies show a beneficial effect of increased IL-1β in the TIME ( 64 ), others show that blockade of IL-1β signaling can prevent immunosuppressive cell recruitment ( 163 ). Other secondary effects of chemotherapy on the immune system are discussed in depth elsewhere ( 40 , 54 ).…”

“…GCN2, an intracellular nutrient sensor, also regulates macrophage function and promotes the pro-tumorigenic phenotype of both TAMs and MDSCs by enhancing translation of the CREB-2/ATF4 transcriptional factor responsible for promoting their differentiation ( 64 ). Fundamentally the changes induced by these altered differentiation pathways results in a pro-tumorigenic response rather than mediating tumor elimination.…”

CD247 Functions as a Prognostic Biomarker for Cutaneous Malignant Melanoma Based on the Analysis of Tumor-immune Microenvironment

“…are attractive targets for immunotherapy. MIF binding to CD74 activates the PI3K/AKT and MAPK signalling pathways, and both these pathways have been related to monocyte immune-suppression and macrophage M2-like polarization to regulate the immune response against metastatic melanoma [26][27][28].…”

The Engagement Between MDSCs and Metastases: Partners in Crime

“…Interestingly, ER stress-inducers like thapsigargin promote in vitro differentiation of human neutrophils to PMN-MDSCs (37). Similarly, GCN2 (general control non-derepressible 2), that is a master environmental sensor able to control transcription and translation in response to nutrient availability, was reported to drive and sustain immunosuppressive functions of MDSCs in tumor microenvironment (50). STAT3 plays a central role in regulating both the expansion and the tolerogenic effects of MDSCs.…”