免疫抑制是食管腺癌 (EAC) 的一个常见特征，并与较差的总生存期 (OS) 相关。我们假设上游因素可能会对 CD3 水平和 T 细胞活性产生负面影响，从而促进免疫抑制和更差的生存。我们使用了从 Barrett's (BE) 发展为不典型增生再到 EAC 患者的临床数据和患者样本，研究了基因 (RNAseq)、蛋白质（组织微阵列）表达并进行了细胞生物学研究，以描绘可能影响 EAC 的影响 CD3 蛋白质稳定性的途径结果。我们发现 CD3-ε 表达和 CD3 T 细胞数量的丧失与 EAC 中较差的 OS 相关。 GRAIL（与淋巴细胞无反应性相关的基因）异构体 1 (GRAIL1) 是 EAC 中的主要异构体，可降解 (ε、γ、δ) CD3 并使 T 细胞失活。相比之下，EAC 中减少的亚型 2 (GRAIL2) 可以稳定 CD3。此外，干扰素刺激基因 15 (ISG15)（一种泛素样蛋白）可促进 GRAIL1 介导的 CD3 降解。因此，连接酶死亡的 GRAIL1 的过表达、ISG15 敲低或缀合缺陷的 ISG15-LRAA 突变体的过表达都可以增加 CD3 水平。我们共同发现，ISG15→GRAIL1→突变的 p53 放大环路会对 CD3 水平和 T 细胞活性产生负面影响，从而促进 EAC 中的免疫抑制。

Immunosuppression is a common feature of esophageal adenocarcinoma (EAC) and has been linked to poor overall survival (OS). We hypothesized that upstream factors might negatively influence CD3 levels and T-cell activity, thus promoting immunosuppression and worse survival. We used clinical data and patient samples of those who progressed from Barrett's (BE) to dysplasia to EAC, investigated gene (RNAseq), protein (tissue microarray) expression and performed cell biology studies to delineate a pathway impacting CD3 protein stability that might influence EAC outcome. We show that the loss of both CD3-ε expression and CD3+ T-cell number are correlated with worse OS in EAC. The GRAIL (gene related to anergy in lymphocytes) isoform 1 (GRAIL1), which is the prominent isoform in EACs, degrades (ε, γ, δ) CD3s and inactivates T-cells. In contrast, isoform 2 (GRAIL2), which is reduced in EACs, stabilizes CD3s. Further, GRAIL1 mediated CD3 degradation is facilitated by interferon stimulated gene 15 (ISG15), a ubiquitin-like protein. Consequently, either the overexpression of a ligase-dead GRAIL1, ISG15 knockdown, or the overexpression of a conjugation-defective ISG15-LRAA mutant can increase CD3 levels. Together, we identified that an ISG15→GRAIL1→mutant p53 amplification loop negatively influencing CD3 levels and T-cell activity, thus promoting immunosuppression in EAC.