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Nicotine promotes M2 macrophage polarization through α5-nAChR/SOX2/CSF-1 axis in lung adenocarcinoma. 尼古丁通过α5-nAChR/SOX2/CSF-1轴促进肺腺癌M2巨噬细胞极化
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03866-4
Guiyu Kang, Hui Song, Lei Bo, Qi Liu, Qiang Li, Jingtan Li, Pan Pan, Jingting Wang, Yanfei Jia, Haiji Sun, Xiaoli Ma

α5-nicotinic acetylcholine receptor (α5-nAChR) plays a vital part in lung adenocarcinoma (LUAD). However, it is not comprehensively understood that how the α5-nAChR affects LUAD. Through diverse bioinformatics analyses and immunohistochemistry, the expressions of α5-nAChR and SOX2 as well as their relations were dissected. α5-nAChR regulated the differentiation of monocytes into M2 macrophages by targeting the STAT3/SOX2/CSF-1 signaling in the coculture system by western blotting and ChIP. α5-nAChR-mediated macrophage-mediated LUAD cell migration via SOX2/CSF-1 signaling in the cocultured medium. Correlations of α5-nAChR, SOX2 and M2 phenotype tumor-associated macrophages (TAMs) were validated in mouse LUAD models and clinical samples. α5-nAChR expression was connected to SOX2 expression, smoking and bad prognosis of LUAD among clinical samples. Nicotine-induced SOX2 expression was mediated by α5-nAChR via STAT3. Additionally, SOX2-mediated macrophage colony-stimulating factor (CSF-1) expression contributed to LUAD progression in vitro. Furthermore, α5-nAChR expression was strongly linked to pSTAT3, SOX2 and M2 macrophage marker CD206 expression and negatively correlated with M1 macrophage marker CD86 expression in vivo. It is indicated that M2 macrophages are mediated by the new α5-nAChR /SOX2/CSF-1 axis in nicotine-related LUAD, which is a potential therapeutic strategy for cancer.

α5-烟碱乙酰胆碱受体(α5-nAChR)在肺腺癌(LUAD)中起着至关重要的作用。然而,人们对α5-nAChR如何影响肺腺癌的认识并不全面。α5-nAChR通过靶向STAT3/SOX2/CSF-1信号,在共培养系统中调控单核细胞向M2巨噬细胞的分化。在共培养培养基中,α5-nAChR 通过 SOX2/CSF-1 信号介导巨噬细胞介导的 LUAD 细胞迁移。在小鼠 LUAD 模型和临床样本中验证了 α5-nAChR、SOX2 和 M2 表型肿瘤相关巨噬细胞(TAMs)的相关性。尼古丁诱导的SOX2表达是由α5-nAChR通过STAT3介导的。此外,SOX2介导的巨噬细胞集落刺激因子(CSF-1)的表达也有助于LUAD在体外的进展。此外,α5-nAChR 的表达与 pSTAT3、SOX2 和 M2 巨噬细胞标记 CD206 的表达密切相关,而与体内 M1 巨噬细胞标记 CD86 的表达呈负相关。研究表明,在尼古丁相关 LUAD 中,M2 巨噬细胞是由新的α5-nAChR /SOX2/CSF-1 轴介导的,这是一种潜在的癌症治疗策略。
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引用次数: 0
New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells. 关于单核细胞衍生树突状细胞上的唾液酸免疫调节潜力的新见解。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03863-7
Zélia Silva, João Amorim Rabaça, Vanessa Luz, Rita Adubeiro Lourenço, Mariolina Salio, Alexandra Couto Oliveira, Pedro Bule, Sebastian Springer, Paula Alexandra Videira

Sialic acids at the cell surface of dendritic cells (DCs) play an important immunomodulatory role, and their manipulation enhances DC maturation, leading to heightened T cell activation. Particularly, at the molecular level, the increased stability of surface MHC-I molecules in monocyte-derived DCs (MoDCs) underpins an improved DC: T cell interaction. In this study, we focused on the impact of sialic acid remodelling by treatment with Clostridium perfringens sialidase on MoDCs' phenotypic and functional characteristics. Our investigation juxtaposes this novel approach with the conventional cytokine-based maturation regimen commonly employed in clinical settings.Notably, C. perfringens sialidase remarkably increased MHC-I levels compared to other sialidases having different specificities, supporting the idea that higher MHC-I is due to the cleavage of specific sialoglycans on cell surface proteins. Sialidase treatment induced rapid elevated surface expression of MHC-I, MHC-II and CD40 within an hour, a response not fully replicated by 48 h cytokine cocktail treatment. These increases were also observable 48 h post sialidase treatment. While CD86 and PD-L1 showed significant increases after 48 h of cytokine maturation, 48 h post sialidase treatment showed a higher increase in CD86 and shorter increase in PD-L1. CCR-7 expression was significantly increased 48 h after sialidase treatment but not significantly affected by cytokine maturation. Both treatments promoted higher secretion of the IL-12 cytokine. However, the cytokine cocktail induced a more pronounced IL-12 production. SNA lectin staining analysis demonstrated that the sialic acid profile is significantly altered by sialidase treatment, but not by the cytokine cocktail, which causes only slight sialic acid upregulation. Notably, the lipid-presenting molecules CD1a, CD1b and CD1c remained unaffected by sialidase treatment in MoDCs, a finding also further supported by experiments performed on C1R cells. Inhibition of endogenous sialidases Neu1 and Neu3 during MoDC differentiation did not affect surface MHC-I expression and cytokine secretion. Yet, sialidase activity in MoDCs was minimal, suggesting that sialidase inhibition does not significantly alter MHC-I-related functions. Our study highlights the unique maturation profile induced by sialic acid manipulation in MoDCs. These findings provide insights into the potential of sialic acid manipulation as a rapid immunomodulatory strategy, offering promising avenues for targeted interventions in inflammatory contexts.

树突状细胞(DC)细胞表面的唾液酸起着重要的免疫调节作用,操纵唾液酸可提高 DC 的成熟度,从而增强 T 细胞的活化。特别是在分子水平上,单核细胞衍生 DC(MoDCs)表面 MHC-I 分子稳定性的增加是改善 DC 与 T 细胞相互作用的基础。在本研究中,我们重点研究了用产气荚膜梭状芽孢杆菌硅糖苷酶处理硅酸重塑对 MoDCs 表型和功能特征的影响。值得注意的是,与其他具有不同特异性的硅糖苷酶相比,产气荚膜梭状芽孢杆菌硅糖苷酶能显著提高 MHC-I 的水平,这支持了一种观点,即更高的 MHC-I 水平是由于细胞表面蛋白上的特定硅糖被裂解所致。硅糖苷酶处理可在一小时内诱导 MHC-I、MHC-II 和 CD40 的表面表达迅速升高,这种反应在细胞因子鸡尾酒处理 48 小时后不能完全复制。硅糖苷酶处理 48 小时后也能观察到这些增加。CD86和PD-L1在细胞因子成熟48小时后显著增加,而在硅糖苷酶处理48小时后,CD86的增加幅度更大,PD-L1的增加幅度更短。硅糖苷酶处理 48 小时后,CCR-7 的表达明显增加,但细胞因子成熟对其影响不大。两种处理方法都能促进 IL-12 细胞因子的分泌。然而,鸡尾酒细胞因子诱导的IL-12分泌更为明显。SNA 凝集素染色分析表明,硅糖苷酶处理会显著改变硅糖酸谱,而细胞因子鸡尾酒则不会,因为后者只会导致硅糖酸轻微上调。值得注意的是,MoDCs 中的脂质呈递分子 CD1a、CD1b 和 CD1c 不受硅糖苷酶处理的影响,这一发现也得到了 C1R 细胞实验的进一步支持。在 MoDC 分化过程中抑制内源性硅糖苷酶 Neu1 和 Neu3 不会影响表面 MHC-I 的表达和细胞因子的分泌。然而,MoDC 中的硅糖苷酶活性极低,这表明硅糖苷酶抑制不会显著改变 MHC-I 相关功能。我们的研究强调了通过操纵硅酸诱导 MoDCs 成熟的独特特征。这些发现让我们了解到了操纵硅唾液酸作为一种快速免疫调节策略的潜力,为在炎症环境中进行有针对性的干预提供了前景广阔的途径。
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引用次数: 0
Phenotypic insights into genetic risk factors for immune-related adverse events in cancer immunotherapy. 癌症免疫疗法中免疫相关不良事件遗传风险因素的表型研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03854-8
Haochuan Ma, Dili Song, Haibo Zhang, Taidong Li, Xing Jin

Background: Immune-related adverse events (irAEs) pose substantial challenges in the realm of cancer immunotherapy, frequently affecting treatment efficacy and patient safety. To address the urgent need for identifying risk factors associated with irAEs, we conducted a comprehensive phenotype-wide Mendelian randomization analysis (MR-PheWAS).

Methods: Utilizing publicly accessible genome-wide association study (GWAS) data, this investigation evaluated the impact of over 5000 exposure variables on susceptibility to irAEs using univariate Mendelian randomization (MR). We categorized these correlations and further explored potential mechanisms by which associated traits might influence irAEs through multivariate MR.

Results: MR-PheWAS identified numerous risk factors for irAEs, encompassing both previously documented and novel associations. Specifically, we identified 105 traits with probable causal relationships to all-grade irAEs and 119 traits with suggestive associations. For high-grade irAEs, we categorized 122 traits as probably associated and 141 as suggestively associated. Notably, multivariate MR analyses uncovered intricate interactions, particularly highlighting how diabetes impacts all-grade irAEs through mediators such as body mass index and sex hormone-binding globulin.

Conclusions: This study has not only identified new risk factors for irAEs but also confirmed several well-established ones. Further investigation is crucial to validate and assess these identified risk factors within clinical trials. A mechanistic understanding of these causal factors is essential for improving the management and prevention of irAEs.

背景:免疫相关不良事件(irAEs)给癌症免疫疗法领域带来了巨大挑战,经常影响治疗效果和患者安全。为了满足确定与irAEs相关的风险因素的迫切需要,我们进行了一项全面的全表型孟德尔随机分析(MR-PheWAS):本研究利用公开的全基因组关联研究(GWAS)数据,采用单变量孟德尔随机分析法(MR)评估了 5000 多个暴露变量对虹膜AEs易感性的影响。我们对这些相关性进行了分类,并通过多变量 MR 进一步探讨了相关性状可能影响虹膜急性损伤的潜在机制:结果:MR-PheWAS 发现了许多虹膜睫状体异常的风险因素,其中既有先前记录的相关因素,也有新发现的相关因素。具体来说,我们发现了 105 个特征与所有等级的虹膜急性心肌梗死可能存在因果关系,119 个特征与虹膜急性心肌梗死有提示性关联。对于高级别虹膜急性心动过速,我们将 122 个性状归类为可能相关,141 个性状归类为提示相关。值得注意的是,多变量磁共振分析发现了错综复杂的相互作用,特别强调了糖尿病如何通过体重指数和性激素结合球蛋白等介导因素影响所有等级的虹膜睫状体异常:这项研究不仅发现了新的虹膜AEs风险因素,还证实了几个已经确立的风险因素。进一步的调查对于在临床试验中验证和评估这些已确定的风险因素至关重要。从机理上理解这些致病因素对于改善虹膜急性心动过速的管理和预防至关重要。
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引用次数: 0
Three-dimensional dynamics of mesothelin-targeted CAR.CIK lymphocytes against ovarian cancer peritoneal carcinomatosis. 间皮素靶向 CAR.CIK 淋巴细胞防治卵巢癌腹膜癌变的三维动态研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03860-w
Federica Galvagno, Valeria Leuci, Annamaria Massa, Chiara Donini, Ramona Rotolo, Sonia Capellero, Alessia Proment, Letizia Vitali, Andrea Maria Lombardi, Valentina Tuninetti, Lorenzo D'Ambrosio, Alessandra Merlini, Elisa Vigna, Giorgio Valabrega, Luca Primo, Alberto Puliafito, Dario Sangiolo

Intraperitoneal cellular immunotherapy with CAR-redirected lymphocytes is an intriguing approach to target peritoneal carcinomatosis (PC) from ovarian cancer (OC), which is currently evaluated in clinical trials. PC displays a composite structure with floating tumor cells within ascites and solid-like masses invading the peritoneum. Therefore, a comprehensive experimental model is crucial to optimize CAR-cell therapies in such a peculiar environment. Here, we explored the activity of cytokine-induced killer lymphocytes (CIK), redirected by CAR against mesothelin (MSLN-CAR.CIK), within reductionistic 3D models resembling the structural complexity of both liquid and solid components of PC. MSLN-CAR.CIK effectively killed and were functionally efficient against OC targets. In a "floating-like" 3D context with floating OC spheroids, both tumor localization and killing by MSLN-CAR.CIK were significantly boosted by fluid flow. In a "solid-like" context, MSLN-CAR.CIK were recruited through the extracellular matrix on embedded tumor aggregates, with variable kinetics depending on the effector-target distance. Furthermore, MSLN-CAR.CIK penetrated the inner levels of OC spheroids exerting effective tumor killing. Our findings provide currently unknown therapeutically relevant information on intraperitoneal approaches with CAR.CIK, supporting further developments and improvements for clinical studies in the context of locoregional cell therapy approaches for patients with PC from OC.

使用 CAR 重定向淋巴细胞的腹膜内细胞免疫疗法是一种针对卵巢癌腹膜癌肿(PC)的有趣方法,目前正在进行临床试验评估。卵巢癌腹膜癌肿显示出一种复合结构,即腹水中漂浮的肿瘤细胞和侵入腹膜的实性肿块。因此,一个全面的实验模型对于在这种特殊环境中优化 CAR 细胞疗法至关重要。在这里,我们探索了细胞因子诱导的杀伤性淋巴细胞(CIK)的活性,CAR 针对间皮素(MSLN-CAR.CIK)重定向的杀伤性淋巴细胞在还原三维模型中的活性,该模型类似于 PC 的液体和固体成分的复杂结构。MSLN-CAR.CIK能有效杀死OC靶标,并具有高效的功能。在浮动 OC 球体的 "浮动类 "三维环境中,流体流动显著促进了 MSLN-CAR.CIK 的肿瘤定位和杀伤作用。在 "类固体 "环境中,MSLN-CAR.CIK通过细胞外基质被吸引到嵌入的肿瘤聚集体上,其动力学变化取决于效应物与靶标的距离。此外,MSLN-CAR.CIK 还能穿透 OC 球体内部,有效杀死肿瘤。我们的研究结果为腹腔内使用 CAR.CIK 的治疗方法提供了目前未知的相关信息,支持了针对 OC PC 患者的局部区域细胞治疗方法临床研究的进一步发展和改进。
{"title":"Three-dimensional dynamics of mesothelin-targeted CAR.CIK lymphocytes against ovarian cancer peritoneal carcinomatosis.","authors":"Federica Galvagno, Valeria Leuci, Annamaria Massa, Chiara Donini, Ramona Rotolo, Sonia Capellero, Alessia Proment, Letizia Vitali, Andrea Maria Lombardi, Valentina Tuninetti, Lorenzo D'Ambrosio, Alessandra Merlini, Elisa Vigna, Giorgio Valabrega, Luca Primo, Alberto Puliafito, Dario Sangiolo","doi":"10.1007/s00262-024-03860-w","DOIUrl":"10.1007/s00262-024-03860-w","url":null,"abstract":"<p><p>Intraperitoneal cellular immunotherapy with CAR-redirected lymphocytes is an intriguing approach to target peritoneal carcinomatosis (PC) from ovarian cancer (OC), which is currently evaluated in clinical trials. PC displays a composite structure with floating tumor cells within ascites and solid-like masses invading the peritoneum. Therefore, a comprehensive experimental model is crucial to optimize CAR-cell therapies in such a peculiar environment. Here, we explored the activity of cytokine-induced killer lymphocytes (CIK), redirected by CAR against mesothelin (MSLN-CAR.CIK), within reductionistic 3D models resembling the structural complexity of both liquid and solid components of PC. MSLN-CAR.CIK effectively killed and were functionally efficient against OC targets. In a \"floating-like\" 3D context with floating OC spheroids, both tumor localization and killing by MSLN-CAR.CIK were significantly boosted by fluid flow. In a \"solid-like\" context, MSLN-CAR.CIK were recruited through the extracellular matrix on embedded tumor aggregates, with variable kinetics depending on the effector-target distance. Furthermore, MSLN-CAR.CIK penetrated the inner levels of OC spheroids exerting effective tumor killing. Our findings provide currently unknown therapeutically relevant information on intraperitoneal approaches with CAR.CIK, supporting further developments and improvements for clinical studies in the context of locoregional cell therapy approaches for patients with PC from OC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"6"},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ly6E on tumor cells impairs anti-tumor T-cell responses: a novel mechanism of tumor-induced immune exclusion. 肿瘤细胞上的 Ly6E 会损害抗肿瘤 T 细胞反应:肿瘤诱导免疫排斥的新机制。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03851-x
Lan Hailin, Chen Yiting, Wu Yue, Li Lijun, Zhang Renlu, Chen Yunhan, Zhu Yanyang, Zhang Qiuyu

Background: Lymphocyte antigen 6 complex, locus E (Ly6E) has been initially demonstrated to involve in T cell activity and impair viral infectivity. Recently, high expression levels of Ly6E have been reported in tumor microenvironment (TME) of various types of cancers. However, the immunoregulatory mechanism of Ly6E manipulating TME remains unknown.

Methods: TCGA database and Kaplan-Meier plotter database were used to evaluate the correlation between Ly6E expression levels and cancer patient survival. After analyzing Ly6E expression levels in human breast cancer tissues and tumor cell lines, we generated Ly6E knockout (KO) and overexpression (OE) mouse cell lines. Cell proliferation ability in vitro and the ability of growth and metastasis in mouse tumor models were compared between KO/OE and wild-type tumor cells. On day 7 after tumor implantation, tumor tissues were separated for flow cytometric assay, bulk RNA sequencing and single-cell RNA sequencing (ScRNA-seq). The role of Ly6E-expressing tumor cell on macrophage was analyzed in vitro.

Results: Our result surprisingly found that high Ly6E expression levels were associated with CD8+ T cell exclusion in tumor tissues and resistance to immunotherapy. Our data showed that knockout of Ly6E in tumor cells prompts tumor regression and inhibits tumor metastases, and Ly6E-OE tumor cells vice versa. The enhanced anti-tumor effect of Ly6E knockout in tumor cells was dependent on T cell response and formed long-lasting memory. The increase in the CD8+ T-cell infiltration into the tumor islet of Ly6E-KO tumors confirmed the role of Ly6E on T cell exclusion. ScRNA-seq analysis showed that M2 macrophages are particularly abundant in the Ly6E-expressing tumor tissues, especially M2-4 macrophage cluster identified by high levels of Arg-1, indicates that Ly6E-expressing tumor cells might restrict T cell infiltration via M2 macrophages. Moreover, in vitro assay showed that cell culture media derived from Ly6E-positive tumor cells promoted macrophage migration and M2 polarization.

Conclusion: Our study illuminated that Ly6E-expressing tumor cells facilitated the accumulation of M2 macrophages in TME, which contributes to CD8+ T cell exclusion and provides new insights for improving efficacy of cancer immunotherapy.

背景:淋巴细胞抗原 6 复合物,位点 E(Ly6E)已被初步证实参与 T 细胞活性并损害病毒的感染性。最近,有报道称 Ly6E 在各种类型癌症的肿瘤微环境(TME)中高水平表达。然而,Ly6E操纵TME的免疫调节机制仍然未知:方法:利用 TCGA 数据库和 Kaplan-Meier plotter 数据库评估 Ly6E 表达水平与癌症患者生存期的相关性。在分析了人类乳腺癌组织和肿瘤细胞系中的 Ly6E 表达水平后,我们生成了 Ly6E 基因敲除(KO)和过表达(OE)小鼠细胞系。比较了 KO/OE 和野生型肿瘤细胞在体外的增殖能力以及在小鼠肿瘤模型中的生长和转移能力。在肿瘤植入后第7天,分离肿瘤组织进行流式细胞分析、大量RNA测序和单细胞RNA测序(ScRNA-seq)。在体外分析了表达 Ly6E 的肿瘤细胞对巨噬细胞的作用:结果:我们惊讶地发现,Ly6E的高表达水平与肿瘤组织中CD8+ T细胞的排斥和对免疫疗法的抵抗有关。我们的数据显示,敲除肿瘤细胞中的 Ly6E 可促使肿瘤消退并抑制肿瘤转移,反之亦然。敲除肿瘤细胞中的 Ly6E 所增强的抗肿瘤作用依赖于 T 细胞反应并形成持久记忆。Ly6E-KO肿瘤的CD8+ T细胞对肿瘤胰岛浸润的增加证实了Ly6E对T细胞排斥的作用。ScRNA-seq分析表明,M2巨噬细胞在Ly6E表达的肿瘤组织中特别丰富,尤其是M2-4巨噬细胞集群,其Arg-1水平很高,这表明Ly6E表达的肿瘤细胞可能通过M2巨噬细胞限制了T细胞的浸润。此外,体外实验表明,来自Ly6E阳性肿瘤细胞的细胞培养基可促进巨噬细胞迁移和M2极化:我们的研究表明,Ly6E表达的肿瘤细胞促进了M2巨噬细胞在TME中的聚集,这有助于CD8+ T细胞的排斥,并为提高癌症免疫疗法的疗效提供了新的见解。
{"title":"Ly6E on tumor cells impairs anti-tumor T-cell responses: a novel mechanism of tumor-induced immune exclusion.","authors":"Lan Hailin, Chen Yiting, Wu Yue, Li Lijun, Zhang Renlu, Chen Yunhan, Zhu Yanyang, Zhang Qiuyu","doi":"10.1007/s00262-024-03851-x","DOIUrl":"10.1007/s00262-024-03851-x","url":null,"abstract":"<p><strong>Background: </strong>Lymphocyte antigen 6 complex, locus E (Ly6E) has been initially demonstrated to involve in T cell activity and impair viral infectivity. Recently, high expression levels of Ly6E have been reported in tumor microenvironment (TME) of various types of cancers. However, the immunoregulatory mechanism of Ly6E manipulating TME remains unknown.</p><p><strong>Methods: </strong>TCGA database and Kaplan-Meier plotter database were used to evaluate the correlation between Ly6E expression levels and cancer patient survival. After analyzing Ly6E expression levels in human breast cancer tissues and tumor cell lines, we generated Ly6E knockout (KO) and overexpression (OE) mouse cell lines. Cell proliferation ability in vitro and the ability of growth and metastasis in mouse tumor models were compared between KO/OE and wild-type tumor cells. On day 7 after tumor implantation, tumor tissues were separated for flow cytometric assay, bulk RNA sequencing and single-cell RNA sequencing (ScRNA-seq). The role of Ly6E-expressing tumor cell on macrophage was analyzed in vitro.</p><p><strong>Results: </strong>Our result surprisingly found that high Ly6E expression levels were associated with CD8<sup>+</sup> T cell exclusion in tumor tissues and resistance to immunotherapy. Our data showed that knockout of Ly6E in tumor cells prompts tumor regression and inhibits tumor metastases, and Ly6E-OE tumor cells vice versa. The enhanced anti-tumor effect of Ly6E knockout in tumor cells was dependent on T cell response and formed long-lasting memory. The increase in the CD8<sup>+</sup> T-cell infiltration into the tumor islet of Ly6E-KO tumors confirmed the role of Ly6E on T cell exclusion. ScRNA-seq analysis showed that M2 macrophages are particularly abundant in the Ly6E-expressing tumor tissues, especially M2-4 macrophage cluster identified by high levels of Arg-1, indicates that Ly6E-expressing tumor cells might restrict T cell infiltration via M2 macrophages. Moreover, in vitro assay showed that cell culture media derived from Ly6E-positive tumor cells promoted macrophage migration and M2 polarization.</p><p><strong>Conclusion: </strong>Our study illuminated that Ly6E-expressing tumor cells facilitated the accumulation of M2 macrophages in TME, which contributes to CD8<sup>+</sup> T cell exclusion and provides new insights for improving efficacy of cancer immunotherapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"4"},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Interdependence of coagulation with immunotherapy and BRAF/MEK inhibitor therapy: results from a prospective study. 凝血与免疫疗法和 BRAF/MEK 抑制剂疗法之间的相互依存关系:一项前瞻性研究的结果。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03850-y
Malte Beckmann, Julian Schlüter, Michael Erdmann, Rafaela Kramer, Sarah Cunningham, Holger Hackstein, Robert Zimmermann, Lucie Heinzerling

Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapies.

免疫检查点抑制剂(ICI)疗法可有效治疗范围不断扩大的癌症实体,但会诱发各种免疫相关副作用(irAEs)。最近的报告表明,ICI 引发的全身炎症与血栓栓塞事件之间存在相关性,而且联合使用抗凝剂可提高疗效。由于癌症患者本身发生血栓事件的风险较高,因此剖析和描述全身性肿瘤疗法诱发促凝血效应的机制及其与抗肿瘤反应的潜在相互作用至关重要。研究人员对接受 ICIs(24 例)或 BRAF/MEK 抑制剂(7 例)治疗的 31 例晚期皮肤癌患者进行了纵向血液和凝血参数评估,这些参数包括开始接受系统性肿瘤治疗前、开始接受系统性肿瘤治疗后 7 天、20 天和 40 天的参数。对两组的变化进行了分析和比较。此外,还研究了凝血参数对无进展生存期、无复发生存期和总生存期的影响。治疗一周后,ICI 组的因子 VIII 活性明显增加(p 0.0225);而在整个观察期间,蛋白 S 活性降低。此外,在免疫疗法中,von Willebrand因子活性和组织因子浓度也有所增加。BRAF/MEK抑制剂疗法(BRAF/MEKi)也发生了类似的变化。在开始接受 ICI 治疗前,von Willebrand 因子抗原和因子 VIII:C 的基线水平升高与接受辅助免疫疗法的患者复发风险显著升高相关。研究结果表明,ICI 和 BRAF/MEKi 会诱导促凝血状态,凝血参数在 ICI 疗法的疗效中发挥作用。
{"title":"Interdependence of coagulation with immunotherapy and BRAF/MEK inhibitor therapy: results from a prospective study.","authors":"Malte Beckmann, Julian Schlüter, Michael Erdmann, Rafaela Kramer, Sarah Cunningham, Holger Hackstein, Robert Zimmermann, Lucie Heinzerling","doi":"10.1007/s00262-024-03850-y","DOIUrl":"10.1007/s00262-024-03850-y","url":null,"abstract":"<p><p>Immune checkpoint inhibitor (ICI) therapies effectively treat a broadening spectrum of cancer entities but induce various immune-related side effects (irAEs). Recent reports suggest a correlation between ICI-induced systemic inflammation and thromboembolic events as well as an increased effectiveness by coadministration of anticoagulants. With cancer patients having a higher risk of thrombotic events per se, it is crucial to dissect and characterize the mechanisms that cause pro-coagulative effects induced by systemic tumor therapies and their potential interplay with anti-tumor response. A total of 31 patients with advanced skin cancer treated with either ICIs (n = 24) or BRAF/MEK inhibitors (n = 7) were longitudinally assessed for blood and coagulation parameters before as well as 7, 20 and 40 days after initiation of systemic tumor therapy. Changes were analyzed and compared between both groups. In addition, the influence of coagulation parameters on progression-free, recurrence-free and overall survival was investigated. The ICI cohort presented significantly increased factor VIII activity after one week of therapy (p 0.0225); while, protein S activity was reduced during the whole observation period. Additionally, von Willebrand factor activity and tissue factor concentrations increased under immunotherapy. Similar changes occurred under BRAF/MEK inhibitor therapy (BRAF/MEKi). Increased baseline levels of von Willebrand factor antigen and factor VIII:C before the start of ICI therapy correlated with a significantly higher risk of recurrence for patients receiving adjuvant immunotherapy. The findings suggest the induction of a pro-coagulant state under ICI and BRAF/MEKi and a role of coagulation parameters in the efficacy of ICI therapies.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"5"},"PeriodicalIF":4.6,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction to: Efficacy and safety of anti‑PD‑1/PD‑L1‑based dual immunotherapies versus PD‑1/PD‑L1 inhibitor alone in patients with advanced solid tumor: a systematic review and meta‑analysis. 更正:基于抗PD-1/PD-L1的双重免疫疗法与单用PD-1/PD-L1抑制剂对晚期实体瘤患者的疗效和安全性:系统综述和荟萃分析。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-16 DOI: 10.1007/s00262-024-03819-x
Yueying Chen, Hedong Han, Jing Cheng, Qinpei Cheng, Suhua Zhu, Ping Zhan, Hongbing Liu, Yong Song, Tangfeng Lv
{"title":"Correction to: Efficacy and safety of anti‑PD‑1/PD‑L1‑based dual immunotherapies versus PD‑1/PD‑L1 inhibitor alone in patients with advanced solid tumor: a systematic review and meta‑analysis.","authors":"Yueying Chen, Hedong Han, Jing Cheng, Qinpei Cheng, Suhua Zhu, Ping Zhan, Hongbing Liu, Yong Song, Tangfeng Lv","doi":"10.1007/s00262-024-03819-x","DOIUrl":"10.1007/s00262-024-03819-x","url":null,"abstract":"","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"263"},"PeriodicalIF":4.6,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Efficacy and safety of perioperative immunotherapy combinations for resectable non-small cell lung cancer: a systematic review and network meta-analysis. 可切除非小细胞肺癌围手术期免疫疗法组合的疗效和安全性:系统综述和网络荟萃分析。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-09 DOI: 10.1007/s00262-024-03844-w
Yuelin Han, Xiangtian Xiao, Tingting Qin, Shuxi Yao, Xinyue Liu, Yanqi Feng, Zhou Li, Yiming Li, Shu Xia

Introduction: Several trials of perioperative immunotherapy for resectable non-small cell lung cancer (NSCLC) reported positive results. They were designed to adjuvant, neoadjuvant and sandwich (neoadjuvant plus adjuvant) immunotherapy with immune checkpoint inhibitors and chemotherapy (CT). The differences between neoadjuvant and sandwich modalities were unclear.

Method: We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, WHO ICTRP and major international conferences.

Results: We analyzed 8 studies involving 3429 patients, including 6 neoadjuvant plus adjuvant (Neo-Adj) and 2 neoadjuvant (Neo) trials. Neo-Adj had better event-free survival (EFS) (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.45-0.71) than CT. There existed no difference between Neo-Adj and Neo in EFS (HR = 0.87, 95% CI: 0.53-1.46) and overall survival (OS) (HR = 1.04, 95% CI: 0.38-2.57). Neo might have lower incidence of treatment-related adverse events (TRAEs) (relative risk [RR] = 0.96, 95% CI: 0.87-1.12) than Neo-Adj. Subgroup analysis of PD-L1 ≥ 50% suggested that EFS of Neo-Adj (HR = 0.46, 95% CI: 0.27-0.76) and Neo (HR = 0.24, 95% CI: 0.06-0.89) was better than CT, and Neo-Adj potentially caused shorter EFS than Neo (HR = 1.92, 95% CI: 0.46-7.84).

Conclusions: Our results suggest that Neo-Adj and Neo have similar EFS for patients with PD-L1 < 1% or 1-49%. However, patients with PD-L1 ≥ 50% may obtain more EFS benefit from Neo than Neo-Adj. Neo might present a more favorable assessment than Neo-Adj when evaluating OS. Moreover, adding adjuvant immunotherapy may increase toxicity.

简介:可切除的非小细胞肺癌(NSCLC)围手术期免疫疗法对可切除的非小细胞肺癌(NSCLC)进行围手术期免疫治疗的几项试验都取得了积极的结果。这些试验设计了辅助、新辅助和夹心(新辅助加辅助)免疫疗法与免疫检查点抑制剂和化疗(CT)。新辅助和三明治模式之间的差异尚不明确:我们从 PubMed、EMBASE、Cochrane Library、Web of Science、ClinicalTrials.gov、WHO ICTRP 和主要国际会议中检索了相关文献,进行了系统综述和贝叶斯网络荟萃分析:我们分析了涉及3429名患者的8项研究,包括6项新辅助加辅助(Neo-Adj)和2项新辅助(Neo)试验。与CT相比,Neo-Adj的无事件生存期(EFS)更好(危险比[HR] = 0.57,95%置信区间[CI]:0.45-0.71)。Neo-Adj 和 Neo 在无事件生存期(HR = 0.87,95% CI:0.53-1.46)和总生存期(OS)(HR = 1.04,95% CI:0.38-2.57)方面没有差异。PD-L1≥50%的亚组分析表明,Neo-Adj的EFS(HR = 0.46,95% CI:0.27-0.76)和Neo(HR = 0.24,95% CI:0.06-0.89)优于CT,Neo-Adj可能导致EFS短于Neo(HR = 1.92,95% CI:0.46-7.84):我们的研究结果表明,Neo-Adj和Neo对PD-L1患者的EFS相似。
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引用次数: 0
Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer. 甲状腺irAE和PD-L1阳性在预测非小细胞肺癌患者PD-1阻断剂疗效中的生物标记作用。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-09 DOI: 10.1007/s00262-024-03852-w
Hye In Kim, Won Gu Kim, Mijin Kim, Nak Gyeong Ko, Mihyeon Jin, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Yoon-La Choi, Min Ji Jeon, Tae Yong Kim, Won Bae Kim, Sang-We Kim, Dae Ho Lee, Se Jin Jang, Sun Wook Kim, Jae Hoon Chung, Tae Hyuk Kim, Se-Hoon Lee

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

甲状腺免疫相关不良事件(irAEs)与程序性细胞死亡蛋白1(PD-1)在非小细胞肺癌(NSCLC)中的阻断疗效有关。然而,它们与 PD-L1 表达的独立性以及对预测 PD-1 阻断疗效的定量影响仍未得到探讨。这项来自韩国的多中心回顾性纵向研究纳入了71例转移性NSCLC患者,他们在PD-1阻断治疗期间接受了PD-L1表达和甲状腺功能检测。根据实体瘤反应评估标准得出的疾病进展是主要结果。分析分为三个阶段:(1)根据甲状腺irAE调整PD-L1表达的多变量Cox回归模型;(2)亚组分析;(3)重新分组并比较当前分期和替代分期的预测性。甲状腺irAE+患者的无进展生存期更长[7/20 vs. 34/51,调整后HR 0.19 (0.07-0.47); P
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引用次数: 0
Optimizing cancer classification: a hybrid RDO-XGBoost approach for feature selection and predictive insights. 优化癌症分类:用于特征选择和预测洞察的 RDO-XGBoost 混合方法。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-09 DOI: 10.1007/s00262-024-03843-x
Abrar Yaqoob, Navneet Kumar Verma, Rabia Musheer Aziz, Mohd Asif Shah

The identification of relevant biomarkers from high-dimensional cancer data remains a significant challenge due to the complexity and heterogeneity inherent in various cancer types. Conventional feature selection methods often struggle to effectively navigate the vast solution space while maintaining high predictive accuracy. In response to these challenges, we introduce a novel feature selection approach that integrates Random Drift Optimization (RDO) with XGBoost, specifically designed to enhance the performance of cancer classification tasks. Our proposed framework not only improves classification accuracy but also offers valuable insights into the underlying biological mechanisms driving cancer progression. Through comprehensive experiments conducted on real-world cancer datasets, including Central Nervous System (CNS), Leukemia, Breast, and Ovarian cancers, we demonstrate the efficacy of our method in identifying a smaller subset of unique and relevant genes. This selection results in significantly improved classification efficiency and accuracy. When compared with popular classifiers such as Support Vector Machine, K-Nearest Neighbor, and Naive Bayes, our approach consistently outperforms these models in terms of both accuracy and F-measure metrics. For instance, our framework achieved an accuracy of 97.24% in the CNS dataset, 99.14% in Leukemia, 95.21% in Ovarian, and 87.62% in Breast cancer, showcasing its robustness and effectiveness across different types of cancer data. These results underline the potential of our RDO-XGBoost framework as a promising solution for feature selection in cancer data analysis, offering enhanced predictive performance and valuable biological insights.

由于各种癌症类型固有的复杂性和异质性,从高维癌症数据中识别相关生物标记物仍然是一项重大挑战。传统的特征选择方法往往难以在保持高预测准确性的同时有效地驾驭广阔的解空间。为了应对这些挑战,我们引入了一种新颖的特征选择方法,它将随机漂移优化(RDO)与 XGBoost 整合在一起,专门用于提高癌症分类任务的性能。我们提出的框架不仅能提高分类准确性,还能为了解驱动癌症进展的潜在生物机制提供宝贵的见解。通过在真实世界癌症数据集(包括中枢神经系统(CNS)、白血病、乳腺癌和卵巢癌)上进行的全面实验,我们证明了我们的方法在识别较小的独特相关基因子集方面的功效。这种选择大大提高了分类效率和准确性。与支持向量机、K-近邻和 Naive Bayes 等流行分类器相比,我们的方法在准确率和 F-measure 指标方面始终优于这些模型。例如,我们的框架在中枢神经系统数据集中的准确率达到了 97.24%,在白血病中达到了 99.14%,在卵巢癌中达到了 95.21%,在乳腺癌中达到了 87.62%,显示了它在不同类型癌症数据中的鲁棒性和有效性。这些结果凸显了我们的 RDO-XGBoost 框架作为癌症数据分析中特征选择的一种有前途的解决方案的潜力,它能提供更高的预测性能和有价值的生物学见解。
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引用次数: 0
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Cancer Immunology, Immunotherapy
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