ATP8B3 作为一种潜在的生物标志物和靶点，用于增强 PD-L1 阻断在结肠腺癌中的治疗效果。
The aminophospholipid transporter, ATP8B3, as a potential biomarker and target for enhancing the therapeutic effect of PD-L1 blockade in colon adenocarcinoma.
机构信息
Department of Interventional Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 's Clinical Research Center for Cancer, Tianjin, China.
出版信息
Genomics. 2024 Sep;116(5):110907. doi: 10.1016/j.ygeno.2024.110907. Epub 2024 Jul 27.
BACKGROUND
Colon adenocarcinoma (COAD) is a prevalent malignant tumor globally, contributing significantly to cancer-related mortality. COAD guidelines label MSI (Microsatellite instability) and MSS (Microsatellite stability) subtypes as global classification criteria and treatment strategy selection criteria for COAD. Various combination therapies involving PD-L1 inhibitors and adjuvant therapy to enhance anti-tumor efficacy.
METHODS
Datasets from single-cell RNA sequencing and bulk RNA sequencing in the TCGA and GEO databases were utilized to identify differentially expressed genes (DEGs). Furthermore, the correlation between ATP8B3 and PD-L1 was validated using siRNA, shRNA, and western blot analysis. Additionally, the association between ATP8B3 and immune checkpoint blockade (ICB) therapy was investigated through immune infiltration analysis and flow cytometry in both in vivo and in vitro assays.
RESULTS
In the COAD patient group, ATP8B3 significantly contributed to the establishment of an immunosuppressive microenvironment. Inhibiting ATP8B3 led to a reduction in PD-L1 expression in colon cancer cell lines. Additionally, ATP8B3 expression levels could serve as a potential guide for PD-L1 treatment in MSI-H COAD patients, with higher ATP8B3 expression associated with increased sensitivity to PD-L1 therapy. However, due to the lack of immuno-killer cells in the microenvironment of MSS subtypes, elevated ATP8B3 expression couldn't increase the sensitivity of MSS COAD patients to PD-L1 inhibitors.
CONCLUSION
Our research results support that Inhibiting ATP8B3 could enhance TIL (tumor-infiltrating lymphocyte) infiltration by reducing PD-L1 expression in MSI-H COAD, thereby serving as an effective strategy to improve PD-L1 blocker efficacy. The treatment strategy of combining ATP8B3 inhibitors and immunotherapy for MSI/MSS COAD patients will be the best choice.
背景
结肠腺癌（COAD）是一种全球流行的恶性肿瘤，对癌症相关死亡率有重大影响。COAD 指南将 MSI（微卫星不稳定）和 MSS（微卫星稳定）亚型标记为 COAD 的全球分类标准和治疗策略选择标准。各种联合疗法涉及 PD-L1 抑制剂和辅助治疗，以增强抗肿瘤疗效。
方法
使用 TCGA 和 GEO 数据库中的单细胞 RNA 测序和批量 RNA 测序数据集来鉴定差异表达基因（DEG）。此外，使用 siRNA、shRNA 和 Western blot 分析验证了 ATP8B3 与 PD-L1 的相关性。此外，通过体内和体外实验中的免疫浸润分析和流式细胞术研究了 ATP8B3 与免疫检查点阻断（ICB）治疗的相关性。
结果
在 COAD 患者组中，ATP8B3 显著有助于建立免疫抑制微环境。抑制 ATP8B3 导致结肠癌细胞系中 PD-L1 表达减少。此外，ATP8B3 表达水平可以作为 MSI-H COAD 患者 PD-L1 治疗的潜在指导，较高的 ATP8B3 表达与对 PD-L1 治疗的敏感性增加相关。然而，由于 MSS 亚型微环境中缺乏免疫杀伤细胞，ATP8B3 表达的升高不能增加 MSS COAD 患者对 PD-L1 抑制剂的敏感性。
结论
我们的研究结果支持抑制 ATP8B3 通过降低 MSI-H COAD 中的 PD-L1 表达来增强 TIL（肿瘤浸润淋巴细胞）浸润，从而成为提高 PD-L1 阻滞剂疗效的有效策略。MSI/MSS COAD 患者联合 ATP8B3 抑制剂和免疫疗法的治疗策略将是最佳选择。
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