尽管信使RNA翻译受到严格调节以保持蛋白质合成和细胞稳态,在几种癌症中长期暴露于干扰素-γ(IFN-γ)可通过吲哚胺-2,3-双加氧酶(IDO)-犬尿氨酸途径导致色氨酸(Trp)短缺,因此通过核糖体移码和色氨酸-苯丙氨酸(W>F)密码子重分配事件(取代子),特别是在Trp密码子处,促进异常肽的产生.然而,Trp耗竭对胃癌(GC)核糖体误译产生异常肽的影响仍不清楚。这里,表明EBV阳性GC中丰富的浸润淋巴细胞持续分泌IFN-γ,IDO1表达上调,导致Trp短缺和W>F替代品的诱导。有趣的是,EBV阳性GC中W>F替代物的产生与抗原呈递和mTOR/eIF4E信号通路的激活有关。抑制mTOR/eIF4E途径或EIF4E表达抵消了W>F代用品的产生和抗原呈递。因此,mTOR/eIF4E途径通过W>F替代事件加速异常肽的产生并增强免疫激活,从而暴露胃癌的脆弱性.这项工作表明,mTOR/eIF4E超激活的EBV阳性GC患者可能受益于抗肿瘤免疫治疗。
Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.