Life Science Institute, Jinzhou Medical University, Jinzhou, China.
Front Immunol. 2022 Aug 17;13:927474. doi: 10.3389/fimmu.2022.927474. eCollection 2022.
Presenilin 1 (PSEN1), as a catalytical core of the γ-secretase complex, plays multiple actions through mediating transmembrane domain shedding of the substrates. Unlike extensive studies performed on investigating the functions of γ-secretase substrates or the effects of γ-secretase inhibitors, our findings uncover a potential action of PSEN1 on PD-L1 alternative truncation and nuclear translocation, broadening our understanding on how the γ-secretase contributes to colon cancer development as well as suggesting a potential strategy to improve the efficacy of PD-1/PD-L1 blockade. Immunohistochemical data showed loss of PD-L1 protein expression in all the primary colon adenocarcioma (COAD) cases in the HPA collection, while PSEN1 was scored to be highly expressed, indicating their converse expression patterns (p<0.001). Meanwhile a strongly positive gene correlation was explored by TIMER2 and GEPIA (p<0.001). Up-regulated PSEN1 expression in COAD might facilitate liberating a C-terminal PD-L1 truncation proteolytic processing. Then following an established regulatory pathway of PD-L1 nuclear translocation, we found that PSEN1 showed significant correlations with multiple components in HDAC2-mediated deacetylation, clathrin-dependent endocytosis, vimentin-associated nucleocytoplasmic shuttling and importin family-mediated nuclear import. Moreover, connections of PSEN1 to the immune response genes transactivated by nuclear PD-L1 were tested. Additionally, contributions of PSEN1 to the tumor invasiveness (p<0.05) and the tumor infiltrating cell enrichments (p<0.001) were investigated by cBioportal and the ESTIMATE algorithm. Levels of PSEN1 were negatively correlated with infiltrating CD8+ T (p<0.05) and CD4+ T helper (Th) 1 cells (p<0.001), while positively correlated with regulatory T cells (Tregs) (p<0.001) and cancer associated fibroblasts (CAFs) (p<0.001). It also displayed significant associations with diverse immune metagenes characteristic of T cell exhaustion, Tregs and CAFs, indicating possible actions in immune escape. Despite still a preliminary stage of this study, we anticipate to deciphering a novel function of PSEN1, and supporting more researchers toward the elucidations of the mechanisms linking the γ-secretase to cancers, which has yet to be fully addressed.
早老素 1（PSEN1）作为γ-分泌酶复合物的催化核心，通过介导底物跨膜结构域的脱落，发挥多种作用。与广泛研究γ-分泌酶底物的功能或γ-分泌酶抑制剂的作用不同，我们的发现揭示了 PSEN1 对 PD-L1 替代截断和核转位的潜在作用，拓宽了我们对γ-分泌酶如何促进结肠癌发展的理解，并为提高 PD-1/PD-L1 阻断的疗效提供了潜在策略。免疫组织化学数据显示，HPA 数据库中所有原发性结肠腺癌（COAD）病例的 PD-L1 蛋白表达缺失，而 PSEN1 评分高表达，表明它们的表达模式相反（p<0.001）。同时，TIMER2 和 GEPIA 探索了强烈的正基因相关性（p<0.001）。COAD 中 PSEN1 的表达上调可能有助于释放 PD-L1 截断蛋白的 C 端蛋白酶加工。然后，遵循 PD-L1 核转位的既定调控途径，我们发现 PSEN1 与 HDAC2 介导的去乙酰化、网格蛋白依赖性内吞、波形蛋白相关的核质穿梭和导入蛋白家族介导的核输入中多个成分显著相关。此外，还测试了 PSEN1 与核 PD-L1 转激活的免疫反应基因的连接。此外，通过 cBioportal 和 ESTIMATE 算法研究了 PSEN1 对肿瘤侵袭性（p<0.05）和肿瘤浸润细胞富集（p<0.001）的贡献。PSEN1 水平与浸润性 CD8+T（p<0.05）和 CD4+辅助性 T（Th）1 细胞（p<0.001）呈负相关，而与调节性 T 细胞（Tregs）（p<0.001）和癌症相关成纤维细胞（CAFs）（p<0.001）呈正相关。它还与 T 细胞耗竭、Tregs 和 CAFs 的多种免疫元基因特征显著相关，表明可能在免疫逃避中发挥作用。尽管这只是这项研究的初步阶段，但我们预计将破译 PSEN1 的新功能，并支持更多的研究人员阐明将γ-分泌酶与癌症联系起来的机制，这尚未得到充分解决。
