Weihao Zhang , Yongjie Xie , Ziyun Liu , Jie Zhang , Bo Ni , Wei Gao , Wenge Xing , Yaoyao Zhou , Tongguo Si
{"title":"氨基磷脂转运体 ATP8B3 作为一种潜在的生物标记物和靶点，可增强 PD-L1 阻断剂对结肠腺癌的治疗效果。","authors":"Weihao Zhang , Yongjie Xie , Ziyun Liu , Jie Zhang , Bo Ni , Wei Gao , Wenge Xing , Yaoyao Zhou , Tongguo Si","doi":"10.1016/j.ygeno.2024.110907","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusion</h3><p>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.</p></div>","PeriodicalId":12521,"journal":{"name":"Genomics","volume":"116 5","pages":"Article 110907"},"PeriodicalIF":3.4000,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0888754324001289/pdfft?md5=5635c02dfd33eab8800ad87fe4783f19&pid=1-s2.0-S0888754324001289-main.pdf","citationCount":"0","resultStr":"{\"title\":\"The aminophospholipid transporter, ATP8B3, as a potential biomarker and target for enhancing the therapeutic effect of PD-L1 blockade in colon adenocarcinoma\",\"authors\":\"Weihao Zhang , Yongjie Xie , Ziyun Liu , Jie Zhang , Bo Ni , Wei Gao , Wenge Xing , Yaoyao Zhou , Tongguo Si\",\"doi\":\"10.1016/j.ygeno.2024.110907\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>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.</p></div><div><h3>Conclusion</h3><p>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.</p></div>\",\"PeriodicalId\":12521,\"journal\":{\"name\":\"Genomics\",\"volume\":\"116 5\",\"pages\":\"Article 110907\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2024-07-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0888754324001289/pdfft?md5=5635c02dfd33eab8800ad87fe4783f19&pid=1-s2.0-S0888754324001289-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genomics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0888754324001289\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genomics","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0888754324001289","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
The aminophospholipid transporter, ATP8B3, as a potential biomarker and target for enhancing the therapeutic effect of PD-L1 blockade in colon adenocarcinoma
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.
期刊介绍：
Genomics is a forum for describing the development of genome-scale technologies and their application to all areas of biological investigation.
As a journal that has evolved with the field that carries its name, Genomics focuses on the development and application of cutting-edge methods, addressing fundamental questions with potential interest to a wide audience. Our aim is to publish the highest quality research and to provide authors with rapid, fair and accurate review and publication of manuscripts falling within our scope.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
