CTLA-4 blockade in ovarian cancer immunotherapy: Mechanisms and clinical strategies

IF 3 3区医学 Q2 ONCOLOGY

Seminars in oncology Pub Date : 2025-06-06 DOI:10.1016/j.seminoncol.2025.152370

Chou-Yi Hsu , Thikra Majid Muhammed , Subasini Uthirapathy , Irfan Ahmad , Suhas Ballal , Rishiv Kalia , Premkumar J , Subhashree Ray , Riyadh Mohammed Mohsin , Abid ALi A. Abiess

{"title":"CTLA-4 blockade in ovarian cancer immunotherapy: Mechanisms and clinical strategies","authors":"Chou-Yi Hsu , Thikra Majid Muhammed , Subasini Uthirapathy , Irfan Ahmad , Suhas Ballal , Rishiv Kalia , Premkumar J , Subhashree Ray , Riyadh Mohammed Mohsin , Abid ALi A. Abiess","doi":"10.1016/j.seminoncol.2025.152370","DOIUrl":null,"url":null,"abstract":"<div><div>Although studies have demonstrated that ovarian cancer cells can express immune checkpoint proteins like CTLA-4 and that higher levels of tumor-infiltrating lymphocytes are linked to better patient survival, clinical trials utilizing immune checkpoint inhibitors in ovarian cancer have not yielded encouraging results. Tumor heterogeneity and innate or acquired resistance associated with the tumor microenvironment (TME) may account for the inadequate response to ICIs. Understanding tumor immunobiology, identifying biomarkers for patient selection, and formulating suitable treatment regimens remain challenging, yet these are the aspirations for the future use of immunotherapy in ovarian cancer. Induced T cells express CD80 and CD86, providing a positive costimulatory signal via CD28. CTLA-4 antagonizes CD28, diminishing T cell activation and modulating the immunological response. Conversely, the negative regulation of CTLA-4 using monoclonal antibodies (mAbs), particularly ipilimumab, may stimulate T-cell responses against ovarian cancer antigens. We elucidate the mechanisms responsible for immunological suppression: T cell exhaustion and senescence in ovarian cancer. We also provide a synopsis of using CTLA-4 monoclonal antibodies in ovarian cancer alone or conjunction with other modalities (eg, chemotherapy). We finally delineate the challenges associated with responding to immunotherapy in ovarian cancer.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152370"},"PeriodicalIF":3.0000,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Seminars in oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0093775425000624","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Although studies have demonstrated that ovarian cancer cells can express immune checkpoint proteins like CTLA-4 and that higher levels of tumor-infiltrating lymphocytes are linked to better patient survival, clinical trials utilizing immune checkpoint inhibitors in ovarian cancer have not yielded encouraging results. Tumor heterogeneity and innate or acquired resistance associated with the tumor microenvironment (TME) may account for the inadequate response to ICIs. Understanding tumor immunobiology, identifying biomarkers for patient selection, and formulating suitable treatment regimens remain challenging, yet these are the aspirations for the future use of immunotherapy in ovarian cancer. Induced T cells express CD80 and CD86, providing a positive costimulatory signal via CD28. CTLA-4 antagonizes CD28, diminishing T cell activation and modulating the immunological response. Conversely, the negative regulation of CTLA-4 using monoclonal antibodies (mAbs), particularly ipilimumab, may stimulate T-cell responses against ovarian cancer antigens. We elucidate the mechanisms responsible for immunological suppression: T cell exhaustion and senescence in ovarian cancer. We also provide a synopsis of using CTLA-4 monoclonal antibodies in ovarian cancer alone or conjunction with other modalities (eg, chemotherapy). We finally delineate the challenges associated with responding to immunotherapy in ovarian cancer.

查看原文本刊更多论文

CTLA-4阻断在卵巢癌免疫治疗中的作用：机制和临床策略

尽管研究表明卵巢癌细胞可以表达免疫检查点蛋白，如CTLA-4，并且更高水平的肿瘤浸润淋巴细胞与更好的患者生存有关，但在卵巢癌中使用免疫检查点抑制剂的临床试验并没有产生令人鼓舞的结果。肿瘤异质性和与肿瘤微环境（TME）相关的先天或获得性耐药可能是对ICIs反应不足的原因。了解肿瘤免疫生物学，确定患者选择的生物标志物，制定合适的治疗方案仍然具有挑战性，但这些都是未来卵巢癌免疫治疗的愿望。诱导T细胞表达CD80和CD86，通过CD28提供正向共刺激信号。CTLA-4可拮抗CD28，减少T细胞活化并调节免疫反应。相反，使用单克隆抗体（mab），特别是ipilimumab对CTLA-4进行负调控，可能会刺激t细胞对卵巢癌抗原的反应。我们阐明了卵巢癌免疫抑制的机制：T细胞衰竭和衰老。我们还提供了使用CTLA-4单克隆抗体在卵巢癌单独或联合其他方式（如化疗）的摘要。我们最后描述了与卵巢癌免疫治疗反应相关的挑战。

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

Seminars in oncology 医学-肿瘤学

CiteScore

6.60

自引率

0.00%

发文量

审稿时长

104 days

期刊介绍： Seminars in Oncology brings you current, authoritative, and practical reviews of developments in the etiology, diagnosis and management of cancer. Each issue examines topics of clinical importance, with an emphasis on providing both the basic knowledge needed to better understand a topic as well as evidence-based opinions from leaders in the field. Seminars in Oncology also seeks to be a venue for sharing a diversity of opinions including those that might be considered "outside the box". We welcome a healthy and respectful exchange of opinions and urge you to approach us with your insights as well as suggestions of topics that you deem worthy of coverage. By helping the reader understand the basic biology and the therapy of cancer as they learn the nuances from experts, all in a journal that encourages the exchange of ideas we aim to help move the treatment of cancer forward.