GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment
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Published on: November 28, 2019
Marie Jo Halaby1,2, Kebria Hezaveh1,2, Sara Lamorte1,2
1Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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.
Insights
Deleting General control nonderepressible 2 (GCN2) in myeloid cells enhances antitumor immunity in melanoma. This shift promotes immune cell activation and improves survival, revealing a new tumor vulnerability.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- General control nonderepressible 2 (GCN2) senses nutrient availability and influences transcription and translation.
- GCN2 is a potential target in immuno-oncology, but its role in tumor immunity is unclear.
- Understanding GCN2's impact on myeloid cells is crucial for developing new cancer therapies.
Purpose of the Study:
- To investigate the functional role of GCN2 in myeloid cells within the melanoma tumor microenvironment.
- To determine how GCN2 signaling affects myeloid cell phenotype and anti-tumor immune responses.
- To explore the therapeutic potential of targeting GCN2 in melanoma.
Main Methods:
- Mass cytometry (CyTOF) and single-cell RNA sequencing were used to analyze myeloid cell phenotypes and immune microenvironment.
- Transcription factor-binding analysis identified key regulatory pathways.
- Small interfering RNA (siRNA) knockdown of ATF4 was performed to assess its role in tumor growth.
- Analysis of patient data correlated GCN2 signatures with clinical outcomes.
Main Results:
- Myeloid-specific deletion of GCN2 promoted anti-tumor immunity by altering macrophage and myeloid-derived suppressor cell (MDSC) phenotypes.
- This led to increased pro-inflammatory activation of myeloid cells and enhanced interferon-γ expression in CD8+ T cells.
- GCN2 signaling, via ATF4 translation, is essential for myeloid cell maturation and polarization.
- Targeting ATF4 reduced tumor growth, and GCN2 signatures in melanoma patients correlated with immune infiltration and survival.
Conclusions:
- Myeloid GCN2 signaling is critical for tumor immune evasion in melanoma.
- Deletion of GCN2 in myeloid cells enhances anti-tumor immunity and may serve as a therapeutic strategy.
- Targeting the GCN2-ATF4 pathway offers a novel approach for melanoma treatment.
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