Revealing the secret behind Epstein-Barr virus-specific tumor immune contexture

IF 20.1 1区 医学 Q1 ONCOLOGY
Chu-Xia Deng
{"title":"Revealing the secret behind Epstein-Barr virus-specific tumor immune contexture","authors":"Chu-Xia Deng","doi":"10.1002/cac2.12529","DOIUrl":null,"url":null,"abstract":"<p>Immune checkpoint inhibitor (ICI) therapy has significantly revolutionized cancer treatment across various malignancies, offering distinct and enduring clinical advantages [<span>1</span>]. Gastric cancer (GC) represents a widespread and life-threatening malignancy with substantial global health implications [<span>2</span>]. However, ICI therapy has not produced satisfactory therapeutic responses in GC patients. Presently, monotherapy targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway demonstrates clinical efficacy in approximately 10% of GC patients [<span>3</span>]. Exploration of novel immunotherapeutic targets is urgently needed. Notably, Epstein-Barr virus (EBV)-positive GC constitutes a distinct GC subset, exhibiting a remarkably higher objective response rate to anti-PD-1 inhibitors—an intriguing phenomenon [<span>4</span>]. Several studies have found that EBV-positive GC has more innate and adaptive immune cell infiltration than EBV-negative GC [<span>5, 6</span>]. In their recent publication titled “Dynamic single-cell mapping reveals Epstein-Barr virus-imprinted T-cell exhaustion and on-treatment response”, Qiu <i>et al.</i> [<span>7</span>] unveiled, for the first time, the cellular basis underlying these remarkably heightened responses in EBV-positive GC patients undergoing immunochemotherapy. Leveraging single-cell profiling technologies, this study deepened our comprehension of the intricate and heterogeneous tumor microenvironment in GC.</p><p>In this study, the authors conducted a comprehensive characterization of the cellular dynamics of tumor-infiltrating immune cells in GC patients, distinguishing between those with EBV-positive and EBV-negative statuses. EBV-positive GC exhibited a heightened immune phenotype characterized by elevated infiltration of T cells and B cells, highlighting the intricate interplay among EBV infection, multi-cellular ecosystems, and tumor development. EBV-negative GC exhibited an immune-suppressive tumor microenvironment characterized by an abundance of plasma cells, myeloid cells, and mast cells. After treatment, the evaluation of the dynamic changes in EBV-positive GC showed an increased presence of cytotoxic CD8<sup>+</sup> T cells and effector memory/memory CD8<sup>+</sup> T cells. Notably, there was clear evidence of clonal revival and reinvigoration of CD8<sup>+</sup> T cells in EBV-positive GC patients, indicating an active T cell-mediated immune reaction enhancing treatment responses.</p><p>Furthermore, the authors observed a distinct EBV-imprinted CD8<sup>+</sup> T cell population, ISG-15<sup>+</sup>CD8<sup>+</sup> T cells, which exhibited significantly higher expression of interferon-stimulated genes, such as ISG-15, IFIT1-3, RASD2, and MX1. Significantly, ISG-15<sup>+</sup>CD8<sup>+</sup> T cells demonstrated the ability to recognize EBV antigens and coordinated exhausted T cell responses. STARTRAC-tran analysis revealed a robust association between ISG-15<sup>+</sup>CD8<sup>+</sup> T cells and actively proliferating T cells, effector CD8<sup>+</sup> T cells (CXCL13<sup>+</sup>CD8<sup>+</sup> T cells) and cytotoxic CD8<sup>+</sup> T cells within EBV-positive GC. It is worth mentioning that EBV epitopes were detected within ISG-15<sup>+</sup>CD8<sup>+</sup> T cells, suggesting that this particular cell population consists of T cells specifically targeting EBV. In the context of ICI-responsive GCs, their investigation revealed a significant proportion of ISG-15<sup>+</sup>CD8<sup>+</sup> T clonotypes prior to treatment within the effector T cell populations of EBV-positive tumors after the treatment. In contrast, there was no evidence of re-emerged clonotypes of pre-existing ISG-15<sup>+</sup>CD8<sup>+</sup> T cells in EBV-negative tumors following therapy. More research is required to validate these observations, as these data suggest that ISG-15<sup>+</sup>CD8<sup>+</sup> T cells function as intermediate precursor exhausted T cells, and fluctuations in the proportions of exhausted T cells and effector T cell populations are associated with the responses to PD-1-based therapies.</p><p>By deciphering the association between the dynamics of ISG-15<sup>+</sup>CD8<sup>+</sup> T cells and clinical response following treatment, the authors discovered that ISG-15<sup>+</sup>CD8<sup>+</sup> T cells could be a significant predictor of a positive treatment response. Their data also revealed that an elevated baseline presence of intratumoral ISG-15<sup>+</sup>CD8<sup>+</sup> T cells may be indicative of a potential benefit from immunochemotherapy. Moreover, ISG15<sup>+</sup>CD8<sup>+</sup> T cell population played a crucial role in the transition to T cell exhaustion, accompanied by escalating levels of LAG-3. In comparison to EBV-negative GC, LAG-3 expression may be upregulated due to an exhaustion expression program triggered by EBV-associated activation. This suggests that LAG-3 could potentially act as a crucial checkpoint for revitalizing the terminal exhausted/dysfunctional T cell subset in EBV-positive GC.</p><p>Moreover, the author described the results of two clinical trials assessing the efficacy of MGD013 and KL-A289 in treating metastatic GC patients. One patient who participated in a phase Ib clinical trial of MGD013, a bi-specific antibody targeting PD-1 and LAG-3, achieved partial response within a month of treatment. Another patient with spleen and multiple lymph node metastases was enrolled in a phase I clinical trial of KL-A289, a LAG-3 inhibitor. After two cycles of KL-A289 treatment, the patient achieved stable disease followed by a significant decrease in the EBV-DNA copy number. These data support further exploration of a LAG-3 antibody in patients with EBV-positive GC and other EBV-associated tumors. Importantly, their longitudinal single-cell view on EBV-positive GC during treatment provided physicians with a direct view on response to treatment, although more detailed investigations on the early effects of anti-LAG-3 and anti-PD-1/PD-L1 are still required. However, the use of biopsies does not allow for direct comparison of the effects of different perturbations, which complicates efforts to answer mechanistic questions. Therefore, alternative approaches that enable direct comparison of the effects of different perturbations should be considered to address this limitation.</p><p>Of note, <i>ex vivo</i> tumor culture systems that maintain the tumor microenvironment and architecture as found in the patient, but that enable perturbation by immunotherapies, offer a unique opportunity to study the dynamics of treatment response and intrinsic properties of a tumor [<span>8</span>]. In particular, air-liquid interface organoids consisting of both tumor and stroma components have been shown to enhance the function of intratumoral T cells on PD-1 blockade [<span>9</span>]. Similarly, various <i>ex vivo</i> models such as patient-derived tumor fragment platform [<span>10</span>], microfluidic cancer-on-chip platform [<span>11</span>], and three-dimensional tumor slice culture platform [<span>12</span>] have been documented with the potential to assess the effect of various antitumor treatment strategies. Using <i>ex vivo</i> tumor culture systems, it is feasible and valuable to assess the effect of anti-LAG3 treatment on the tumor microenvironment and thereby directly test the functional importance of specific cell types in the treatment response.</p><p>Overall, this study represents a significant advancement in our understanding of the EBV-specific tumor immune contexture. The authors propose that the ISG15<sup>+</sup>CD8<sup>+</sup> T cell signature may predict a good response to immunotherapy. More importantly, their findings reveal the necessity of dual blockade of PD-1 and LAG-3 in EBV-associated GC (Figure 1). The comprehensive insights gained from this research pave the way for future research aimed at developing innovative and personalized therapeutic approaches in the fight against cancer.</p><p>Chu-Xia Deng wrote and proofread the manuscript.</p><p>The authors declare that they have no competing interests.</p><p>Not applicable.</p><p>Not applicable.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":20.1000,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12529","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Communications","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cac2.12529","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Immune checkpoint inhibitor (ICI) therapy has significantly revolutionized cancer treatment across various malignancies, offering distinct and enduring clinical advantages [1]. Gastric cancer (GC) represents a widespread and life-threatening malignancy with substantial global health implications [2]. However, ICI therapy has not produced satisfactory therapeutic responses in GC patients. Presently, monotherapy targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway demonstrates clinical efficacy in approximately 10% of GC patients [3]. Exploration of novel immunotherapeutic targets is urgently needed. Notably, Epstein-Barr virus (EBV)-positive GC constitutes a distinct GC subset, exhibiting a remarkably higher objective response rate to anti-PD-1 inhibitors—an intriguing phenomenon [4]. Several studies have found that EBV-positive GC has more innate and adaptive immune cell infiltration than EBV-negative GC [5, 6]. In their recent publication titled “Dynamic single-cell mapping reveals Epstein-Barr virus-imprinted T-cell exhaustion and on-treatment response”, Qiu et al. [7] unveiled, for the first time, the cellular basis underlying these remarkably heightened responses in EBV-positive GC patients undergoing immunochemotherapy. Leveraging single-cell profiling technologies, this study deepened our comprehension of the intricate and heterogeneous tumor microenvironment in GC.

In this study, the authors conducted a comprehensive characterization of the cellular dynamics of tumor-infiltrating immune cells in GC patients, distinguishing between those with EBV-positive and EBV-negative statuses. EBV-positive GC exhibited a heightened immune phenotype characterized by elevated infiltration of T cells and B cells, highlighting the intricate interplay among EBV infection, multi-cellular ecosystems, and tumor development. EBV-negative GC exhibited an immune-suppressive tumor microenvironment characterized by an abundance of plasma cells, myeloid cells, and mast cells. After treatment, the evaluation of the dynamic changes in EBV-positive GC showed an increased presence of cytotoxic CD8+ T cells and effector memory/memory CD8+ T cells. Notably, there was clear evidence of clonal revival and reinvigoration of CD8+ T cells in EBV-positive GC patients, indicating an active T cell-mediated immune reaction enhancing treatment responses.

Furthermore, the authors observed a distinct EBV-imprinted CD8+ T cell population, ISG-15+CD8+ T cells, which exhibited significantly higher expression of interferon-stimulated genes, such as ISG-15, IFIT1-3, RASD2, and MX1. Significantly, ISG-15+CD8+ T cells demonstrated the ability to recognize EBV antigens and coordinated exhausted T cell responses. STARTRAC-tran analysis revealed a robust association between ISG-15+CD8+ T cells and actively proliferating T cells, effector CD8+ T cells (CXCL13+CD8+ T cells) and cytotoxic CD8+ T cells within EBV-positive GC. It is worth mentioning that EBV epitopes were detected within ISG-15+CD8+ T cells, suggesting that this particular cell population consists of T cells specifically targeting EBV. In the context of ICI-responsive GCs, their investigation revealed a significant proportion of ISG-15+CD8+ T clonotypes prior to treatment within the effector T cell populations of EBV-positive tumors after the treatment. In contrast, there was no evidence of re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells in EBV-negative tumors following therapy. More research is required to validate these observations, as these data suggest that ISG-15+CD8+ T cells function as intermediate precursor exhausted T cells, and fluctuations in the proportions of exhausted T cells and effector T cell populations are associated with the responses to PD-1-based therapies.

By deciphering the association between the dynamics of ISG-15+CD8+ T cells and clinical response following treatment, the authors discovered that ISG-15+CD8+ T cells could be a significant predictor of a positive treatment response. Their data also revealed that an elevated baseline presence of intratumoral ISG-15+CD8+ T cells may be indicative of a potential benefit from immunochemotherapy. Moreover, ISG15+CD8+ T cell population played a crucial role in the transition to T cell exhaustion, accompanied by escalating levels of LAG-3. In comparison to EBV-negative GC, LAG-3 expression may be upregulated due to an exhaustion expression program triggered by EBV-associated activation. This suggests that LAG-3 could potentially act as a crucial checkpoint for revitalizing the terminal exhausted/dysfunctional T cell subset in EBV-positive GC.

Moreover, the author described the results of two clinical trials assessing the efficacy of MGD013 and KL-A289 in treating metastatic GC patients. One patient who participated in a phase Ib clinical trial of MGD013, a bi-specific antibody targeting PD-1 and LAG-3, achieved partial response within a month of treatment. Another patient with spleen and multiple lymph node metastases was enrolled in a phase I clinical trial of KL-A289, a LAG-3 inhibitor. After two cycles of KL-A289 treatment, the patient achieved stable disease followed by a significant decrease in the EBV-DNA copy number. These data support further exploration of a LAG-3 antibody in patients with EBV-positive GC and other EBV-associated tumors. Importantly, their longitudinal single-cell view on EBV-positive GC during treatment provided physicians with a direct view on response to treatment, although more detailed investigations on the early effects of anti-LAG-3 and anti-PD-1/PD-L1 are still required. However, the use of biopsies does not allow for direct comparison of the effects of different perturbations, which complicates efforts to answer mechanistic questions. Therefore, alternative approaches that enable direct comparison of the effects of different perturbations should be considered to address this limitation.

Of note, ex vivo tumor culture systems that maintain the tumor microenvironment and architecture as found in the patient, but that enable perturbation by immunotherapies, offer a unique opportunity to study the dynamics of treatment response and intrinsic properties of a tumor [8]. In particular, air-liquid interface organoids consisting of both tumor and stroma components have been shown to enhance the function of intratumoral T cells on PD-1 blockade [9]. Similarly, various ex vivo models such as patient-derived tumor fragment platform [10], microfluidic cancer-on-chip platform [11], and three-dimensional tumor slice culture platform [12] have been documented with the potential to assess the effect of various antitumor treatment strategies. Using ex vivo tumor culture systems, it is feasible and valuable to assess the effect of anti-LAG3 treatment on the tumor microenvironment and thereby directly test the functional importance of specific cell types in the treatment response.

Overall, this study represents a significant advancement in our understanding of the EBV-specific tumor immune contexture. The authors propose that the ISG15+CD8+ T cell signature may predict a good response to immunotherapy. More importantly, their findings reveal the necessity of dual blockade of PD-1 and LAG-3 in EBV-associated GC (Figure 1). The comprehensive insights gained from this research pave the way for future research aimed at developing innovative and personalized therapeutic approaches in the fight against cancer.

Chu-Xia Deng wrote and proofread the manuscript.

The authors declare that they have no competing interests.

Not applicable.

Not applicable.

Abstract Image

揭示 Epstein-Barr 病毒特异性肿瘤免疫背景背后的秘密。
免疫检查点抑制剂(ICI)疗法为各种恶性肿瘤的癌症治疗带来了重大变革,具有独特而持久的临床优势[1]。胃癌(GC)是一种广泛存在且危及生命的恶性肿瘤,对全球健康具有重大影响[2]。然而,ICI疗法并未对胃癌患者产生令人满意的治疗效果。目前,针对程序性细胞死亡蛋白 1/程序性死亡配体 1(PD-1/PD-L1)通路的单一疗法对大约 10% 的 GC 患者有临床疗效 [3]。新型免疫治疗靶点的探索迫在眉睫。值得注意的是,Epstein-Barr 病毒(EBV)阳性 GC 是一个独特的 GC 亚群,对抗 PD-1 抑制剂的客观反应率明显更高--这是一个耐人寻味的现象 [4]。多项研究发现,与 EBV 阴性 GC 相比,EBV 阳性 GC 有更多的先天性和适应性免疫细胞浸润[5, 6]。在最近发表的题为 "动态单细胞图谱揭示 Epstein-Barr 病毒印迹 T 细胞衰竭和治疗反应 "的文章中,Qiu 等人[7]首次揭示了接受免疫化疗的 EBV 阳性 GC 患者显著增强反应的细胞基础。在这项研究中,作者对 GC 患者肿瘤浸润免疫细胞的细胞动态进行了全面描述,并对 EBV 阳性和 EBV 阴性患者进行了区分。EBV 阳性 GC 表现出以 T 细胞和 B 细胞浸润增加为特征的高度免疫表型,突显了 EBV 感染、多细胞生态系统和肿瘤发生之间错综复杂的相互作用。EBV 阴性 GC 表现出以大量浆细胞、髓细胞和肥大细胞为特征的免疫抑制性肿瘤微环境。治疗后,对 EBV 阳性 GC 动态变化的评估显示,细胞毒性 CD8+ T 细胞和效应记忆/记忆 CD8+ T 细胞的数量有所增加。值得注意的是,有明确证据表明,EBV 阳性 GC 患者的 CD8+ T 细胞克隆复兴和重新活跃,这表明 T 细胞介导的免疫反应活跃,增强了治疗反应。此外,作者还观察到一种独特的 EBV 印迹 CD8+ T 细胞群,即 ISG-15+CD8+ T 细胞,它们的干扰素刺激基因(如 ISG-15、IFIT1-3、RASD2 和 MX1)表达量明显更高。值得注意的是,ISG-15+CD8+ T 细胞具有识别 EBV 抗原和协调衰竭 T 细胞反应的能力。STARTRAC-tran 分析显示,在 EBV 阳性的 GC 中,ISG-15+CD8+ T 细胞与活跃增殖的 T 细胞、效应 CD8+ T 细胞(CXCL13+CD8+ T 细胞)和细胞毒性 CD8+ T 细胞之间存在密切联系。值得一提的是,在 ISG-15+CD8+ T 细胞中检测到了 EBV 表位,这表明这一特殊细胞群由特异性靶向 EBV 的 T 细胞组成。就 ICI 反应性 GC 而言,他们的研究发现,治疗前的 ISG-15+CD8+ T 克隆型细胞在治疗后 EBV 阳性肿瘤的效应 T 细胞群中占很大比例。与此相反,在治疗后的EBV阴性肿瘤中,没有证据表明之前存在的ISG-15+CD8+ T细胞克隆重新出现。这些数据表明,ISG-15+CD8+ T 细胞具有作为衰竭 T 细胞中间前体的功能,而衰竭 T 细胞和效应 T 细胞群比例的波动与对基于 PD-1 疗法的反应有关。通过解读 ISG-15+CD8+ T 细胞的动态与治疗后临床反应之间的关联,作者发现 ISG-15+CD8+ T 细胞可以显著预测积极的治疗反应。他们的数据还显示,瘤内ISG-15+CD8+ T细胞基线的升高可能预示着免疫化疗的潜在获益。此外,ISG15+CD8+ T细胞群在T细胞衰竭的过渡过程中发挥了关键作用,并伴随着LAG-3水平的升高。与 EBV 阴性的 GC 相比,LAG-3 的表达可能会因 EBV 相关激活引发的衰竭表达程序而上调。这表明,LAG-3 有可能成为振兴 EBV 阳性 GC 中末期衰竭/功能障碍 T 细胞亚群的关键检查点。此外,作者还描述了两项临床试验的结果,评估了 MGD013 和 KL-A289 治疗转移性 GC 患者的疗效。MGD013是一种靶向PD-1和LAG-3的双特异性抗体,一名参加Ib期临床试验的患者在治疗一个月后获得了部分应答。
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
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
文献相关原料
公司名称 产品信息 采购帮参考价格
×
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