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Loss of Anti-Tumor Efficacy by Polyamine Blocking Therapy in GCN2 Null Mice
Eric T Alexander1, Erin Fahey1, Otto Phanstiel2
1Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
Abstract:
GCN2 is one of the main sensors of amino acid starvation stress, and its activation in the stressful tumor microenvironment plays a crucial role in tumor survival and progression. We hypothesized that elevated polyamine biosynthesis and subsequent depletion of precursor arginine activates GCN2, thus rewiring metabolism to support tumor cell survival and drive myeloid immunosuppressive function. We sought to determine if the anti-tumor efficacy of a polyamine blocking therapy (PBT) may be mediated by its effect on GCN2. Unlike wild-type mice, PBT treatment in GCN2 knockout mice bearing syngeneic B16.F10 or EG7 tumors resulted in no tumor growth inhibition and no changes in the profile of infiltrating tumor immune cells. Studies with murine bone marrow cell cultures showed that increased polyamine metabolism and subsequent arginine depletion and GCN2 activation played an essential role in the generation and cytoprotective autophagy of myeloid derived suppressor cells (MDSCs) as well as the M2 polarization and survival of macrophages, all of which were inhibited by PBT. In all, our data suggest that polyamine-dependent GCN2 signaling in stromal cells promotes tumor growth and the development of the immunosuppressive tumor microenvironment, and that the PBT anti-tumor effect is mediated, at least in part, by targeting GCN2.
Insights
Polyamines and arginine metabolism activate GCN2, promoting tumor growth and immune suppression. Polyamine blocking therapy (PBT) inhibits tumors by targeting GCN2, impacting myeloid-derived suppressor cells and macrophages.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- General Control Nonderepressible 2 (GCN2) kinase senses amino acid starvation.
- Tumor microenvironments activate GCN2, aiding tumor survival and progression.
- Polyamines and arginine metabolism are implicated in tumor growth and immune evasion.
Purpose of the Study:
- To investigate if polyamine biosynthesis and arginine depletion activate GCN2.
- To determine if polyamine blocking therapy (PBT) efficacy relies on GCN2 inhibition.
- To elucidate the role of GCN2 in myeloid-derived suppressor cells (MDSCs) and macrophages within the tumor microenvironment.
Main Methods:
- Utilized GCN2 knockout and wild-type mice with syngeneic B16.F10 or EG7 tumors.
- Administered polyamine blocking therapy (PBT) to assess anti-tumor efficacy.
- Analyzed murine bone marrow cell cultures to study polyamine metabolism, arginine depletion, GCN2 activation, MDSC generation, autophagy, and macrophage polarization.
Main Results:
- PBT failed to inhibit tumor growth in GCN2 knockout mice, unlike in wild-type mice.
- PBT treatment altered the profile of infiltrating immune cells in wild-type but not GCN2 knockout mice.
- Arginine depletion and GCN2 activation were essential for MDSC generation, cytoprotective autophagy, M2 macrophage polarization, and survival, all inhibited by PBT.
Conclusions:
- Polyamine-dependent GCN2 signaling in stromal cells drives tumor growth and immunosuppression.
- PBT exerts anti-tumor effects, at least partially, by targeting GCN2.
- GCN2 plays a critical role in regulating immune cell function within the tumor microenvironment.
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