Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A Shah, Anne M Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W Blaser, William E Carson
{"title":"Inhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors.","authors":"Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A Shah, Anne M Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W Blaser, William E Carson","doi":"10.1172/jci.insight.169927","DOIUrl":null,"url":null,"abstract":"<p><p>BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 21","pages":""},"PeriodicalIF":6.3000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601564/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCI insight","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/jci.insight.169927","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.
背景用伊布替尼抑制布鲁顿酪氨酸激酶可阻断髓源性抑制细胞(MDSC)的功能。方法16名患者在28天周期的第1天和第15天每天接受伊布替尼420毫克静脉滴注,同时接受尼妥珠单抗240毫克静脉滴注。测量了伊布替尼和 nivolumab 对 MDSC、免疫概况和细胞因子水平的影响。对免疫细胞进行了单细胞RNA-Seq和T细胞受体测序。4名患者有部分反应,4名患者在3个月时病情稳定(平均6.5个月,范围3.5-14.6)。中位总生存期(OS)为10.8个月。布鲁顿酪氨酸激酶(BTK)抑制七天可显著增加单核细胞-MDSC(M-MDSC)的比例,并显著减少与MDSC募集和聚集相关的趋化因子(CCL2、CCL3、CCL4、CCL13)。单细胞RNA-Seq显示,伊布替尼诱导下调了与MDSC抑制功能相关的基因(TIMP1、CXCL8、VEGFA、HIF1A),减少了MDSC与衰竭的CD8+ T细胞的相互作用,并降低了TCR复合物的多样性。加入 nivolumab 能显著增加循环中的 NK 和 CD8+ T 细胞,并增加 CD8+ T 细胞的增殖。探索性分析表明,根据患者的反应,BTK抑制对MDSC和T细胞基因表达及TCR复合物多样性的影响不同。
期刊介绍:
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.