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 Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

An Insight into the Roles of Dietary Tryptophan and Its Metabolites in Intestinal Inflammation and Inflammatory Bowel Disease

“…[ 66,73 ] For example, the activation of GCN2 signaling pathway by IDO1‐mediated Trp depletion can block the translation of IL‐6 mRNA in murine plasmacytoid DCs, and triggered differentiation and recruitment of T‐regs. [ 69,70 ] Also, the reduction of CD8 + T‐cell activation and necrosis was observed in the absence of Trp due to GCN2 deficiency [ 65 ] and with the upregulation of tryptophanyl‐tRNA synthetase via IFN‐γ and/or GCN2‐dependent phosphorylation of eIF2α and induction of ATF4 signaling protected Trp‐degrading cancer cells. [ 176 ] Moreover, mTOR signaling reduces when the Trp is limiting, and then T cells fail to proliferate in response to antigen.…”

“…[64] Activation of the GCN2 signaling pathway with Trp depletion and KYN production has been implicated in the immune response by affecting the functions of immune cells. [53,65] For example, GCN2 deficiency significantly decreases T-cell activation and cytokine production, whereas GCN2 activation can promote cell autophagy and antigen cross-presentation, thereby enhancing virus-specific CD8 + T cell response. [66][67][68] Additionally, IDO1-mediated Trp depletion activates GCN2 signaling system that in turn triggers differentiation and recruitment of T-regs.…”

Hypomodified tRNA in evolutionarily distant yeasts can trigger rapid tRNA decay to activate the general amino acid control response, but with different consequences

“…In S. pombe trm8Δ mutants, activation of the GAAC response exacerbates the growth defect, as mutation of any of four components (gcn1, gcn2, tif221, or fil1) protects against loss of tRNA. Activation of the GAAC pathway is also part of the reason that S. cerevisiae trm7Δ mutants grow poorly [83], and defects in the integrated stress response pathway (ISR) in humans are implicated in disease phenotypes [109][110][111]. By contrast, in S. cerevisiae trm8Δ trm4Δ mutants, activation of the GAAC response rescues the growth defect, as deletion of any of three GAAC components (gcn1Δ, gcn2Δ, or gcn4Δ) exacerbates the growth defect.…”

Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma

“…Brain tumors exist in a harsh environment consisting of severe hypoxia ( 15 ), extracellular acidification ( 16 – 18 ), and nutrient competition ( 19 , 20 ). Hypoxia and acidity enhance both cancer aggressiveness ( 21 ) and immunosuppression ( 22 , 23 ).…”