GCN2 is essential for CD8+ T cell survival and function in murine models of malignant glioma.

Abstract

Amino acid deprivation is a strategy that malignancies utilize to blunt anti-tumor T-cell immune responses. It has been proposed that amino acid insufficiency in T-cells is detected by GCN2 kinase, which through phosphorylation of EIF2α, shuts down global protein synthesis leading to T-cell arrest. The role of this amino acid stress sensor in the context of malignant brain tumors has not yet been studied, and may elucidate important insights into the mechanisms of T-cell survival in this harsh environment. Using animal models of glioblastoma and animals with deficiency in GCN2, we explored the importance of this pathway in T-cell function within brain tumors. Our results show that GCN2 deficiency limited CD8+ T-cell activation and expression of cytotoxic markers in two separate murine models of glioblastoma in vivo. Importantly, adoptive transfer of antigen-specific T-cells from GCN2 KO mice did not control tumor burden as well as wild-type CD8+ T-cells. Our in vitro and in vivo data demonstrated that reduction in amino acid availability caused GCN2 deficient CD8+ T-cells to become rapidly necrotic. Mechanistically, reduced CD8+ T-cell activation and necrosis was due to a disruption in TCR signaling, as we observed reductions in PKCθ and phoshpo-PKCθ on CD8+ T-cells from GCN2 KO mice in the absence of tryptophan. Validating these observations, treatment of wild-type CD8+ T-cells with a downstream inhibitor of GCN2 activation also triggered necrosis of CD8+ T-cells in the absence of tryptophan. In conclusion, our data demonstrate the vital importance of intact GCN2 signaling on CD8+ T-cell function and survival in glioblastoma.

• Authors: Aida Rashidi, Jason Miska, Catalina Lee-Chang, Deepak Kanojia, Wojciech K Panek, Aurora Lopez-Rosas, Peng Zhang, Yu Han, Ting Xiao, Katarzyna C Pituch, Julius W Kim, Mahsa Talebian, Jawad Fares, Maciej S Lesniak
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 69 Issue 1 Pg. 81-94 (Jan 2020) ISSN: 1432-0851 [Electronic] Germany
• PMID: 31844909 (Publication Type: Journal Article)

Chemical References

• Eif2ak4 protein, mouse
• Protein Serine-Threonine Kinases
• eIF2alpha kinase, mouse

Topics

• Adoptive Transfer
• Animals
• Brain Neoplasms (immunology, pathology, therapy)
• CD8-Positive T-Lymphocytes (immunology, pathology, transplantation)
• Cell Line, Tumor (transplantation)
• Cell Survival (immunology)
• Disease Models, Animal
• Glioblastoma (immunology, pathology, therapy)
• Humans
• Lymphocyte Activation
• Mice
• Mice, Knockout
• Necrosis (genetics, immunology)
• Phosphorylation (immunology)
• Protein Biosynthesis (immunology)
• Protein Serine-Threonine Kinases (genetics, immunology, metabolism)
• Tumor Escape (immunology)