Antibody blockade of the PSGL-1 immune checkpoint enhances T-cell responses to B-cell lymphoma

IF 12.8 1区 医学 Q1 HEMATOLOGY
João L. Pereira, Liliana Arede, Francisca Ferreira, Andreia Matos, Dulcineia Pereira, Rita F. Santos, Alexandre M. Carmo, Maria J. Oliveira, José C. Machado, Delfim Duarte, Nuno R. dos Santos
{"title":"Antibody blockade of the PSGL-1 immune checkpoint enhances T-cell responses to B-cell lymphoma","authors":"João L. Pereira, Liliana Arede, Francisca Ferreira, Andreia Matos, Dulcineia Pereira, Rita F. Santos, Alexandre M. Carmo, Maria J. Oliveira, José C. Machado, Delfim Duarte, Nuno R. dos Santos","doi":"10.1038/s41375-024-02446-w","DOIUrl":null,"url":null,"abstract":"<p>Despite advancements in cancer immunotherapy, most lymphomas remain unresponsive to checkpoint inhibitors. P-selectin glycoprotein ligand-1 (PSGL-1), recently identified as a promoter of T-cell exhaustion in murine melanoma models, has emerged as a novel immune checkpoint protein and promising immunotherapeutic target. In this study, we investigated the potential of PSGL-1 antibody targeting in B-cell lymphoma. Using allogeneic co-culture systems, we demonstrated that targeted antibody interventions against human PSGL-1 enhanced T-cell activation and effector cytokine production in response to lymphoma cells. Moreover, in vitro treatment of primary lymphoma cell suspensions with PSGL-1 antibody resulted in increased activation of autologous lymphoma-infiltrating T cells. Using the A20 syngeneic B-cell lymphoma mouse model, we found that PSGL-1 antibody treatment significantly slowed tumor development and reduced the endpoint tumor burden. This antitumoral effect was accompanied by augmented tumor infiltration of CD4<sup>+</sup> and CD8<sup>+</sup> T cells and reduced infiltration of regulatory T cells. Finally, anti-PSGL-1 administration enhanced the expansion of CAR T cells previously transferred to mice bearing the aggressive Eμ-<i>Myc</i> lymphoma cells and improved disease control. These results demonstrate that PSGL-1 antibody blockade bolsters T-cell activity against B-cell lymphoma, suggesting a potential novel immunotherapeutic approach for treating these malignancies.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"194 1","pages":""},"PeriodicalIF":12.8000,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41375-024-02446-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Despite advancements in cancer immunotherapy, most lymphomas remain unresponsive to checkpoint inhibitors. P-selectin glycoprotein ligand-1 (PSGL-1), recently identified as a promoter of T-cell exhaustion in murine melanoma models, has emerged as a novel immune checkpoint protein and promising immunotherapeutic target. In this study, we investigated the potential of PSGL-1 antibody targeting in B-cell lymphoma. Using allogeneic co-culture systems, we demonstrated that targeted antibody interventions against human PSGL-1 enhanced T-cell activation and effector cytokine production in response to lymphoma cells. Moreover, in vitro treatment of primary lymphoma cell suspensions with PSGL-1 antibody resulted in increased activation of autologous lymphoma-infiltrating T cells. Using the A20 syngeneic B-cell lymphoma mouse model, we found that PSGL-1 antibody treatment significantly slowed tumor development and reduced the endpoint tumor burden. This antitumoral effect was accompanied by augmented tumor infiltration of CD4+ and CD8+ T cells and reduced infiltration of regulatory T cells. Finally, anti-PSGL-1 administration enhanced the expansion of CAR T cells previously transferred to mice bearing the aggressive Eμ-Myc lymphoma cells and improved disease control. These results demonstrate that PSGL-1 antibody blockade bolsters T-cell activity against B-cell lymphoma, suggesting a potential novel immunotherapeutic approach for treating these malignancies.

Abstract Image

抗体阻断 PSGL-1 免疫检查点可增强 T 细胞对 B 细胞淋巴瘤的反应
尽管癌症免疫疗法取得了进展,但大多数淋巴瘤对检查点抑制剂仍无反应。P-选择素糖蛋白配体-1(P-selectin glycoprotein ligand-1,PSGL-1)最近被确定为小鼠黑色素瘤模型中T细胞衰竭的促进因子,它已成为一种新型免疫检查点蛋白和有希望的免疫治疗靶点。在这项研究中,我们探讨了 PSGL-1 抗体靶向治疗 B 细胞淋巴瘤的潜力。利用异体共培养系统,我们证明了针对人 PSGL-1 的靶向抗体干预能增强 T 细胞的活化和效应细胞因子的产生,以应对淋巴瘤细胞。此外,用 PSGL-1 抗体体外处理原代淋巴瘤细胞悬浮液可增强自体淋巴瘤浸润 T 细胞的活化。通过使用 A20 合成 B 细胞淋巴瘤小鼠模型,我们发现 PSGL-1 抗体治疗能显著减缓肿瘤的发展并减少终点肿瘤负荷。这种抗肿瘤效应伴随着 CD4+ 和 CD8+ T 细胞的肿瘤浸润增加和调节性 T 细胞浸润的减少。最后,服用抗 PSGL-1 能增强先前转移到携带侵袭性 Eμ-Myc 淋巴瘤细胞小鼠体内的 CAR T 细胞的扩增,并改善疾病控制。这些结果表明,PSGL-1 抗体阻断增强了 T 细胞对抗 B 细胞淋巴瘤的活性,为治疗这些恶性肿瘤提供了一种潜在的新型免疫治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信