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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。
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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。
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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。
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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
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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 4.6 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。
{"title":"Efficacy and safety of perioperative immunotherapy combinations for resectable non-small cell lung cancer: a systematic review and network meta-analysis.","authors":"Yuelin Han, Xiangtian Xiao, Tingting Qin, Shuxi Yao, Xinyue Liu, Yanqi Feng, Zhou Li, Yiming Li, Shu Xia","doi":"10.1007/s00262-024-03844-w","DOIUrl":"10.1007/s00262-024-03844-w","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Method: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388274","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
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 4.6 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
{"title":"Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer.","authors":"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","doi":"10.1007/s00262-024-03852-w","DOIUrl":"10.1007/s00262-024-03852-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388273","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
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 4.6 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
Increased myositis and possible myocarditis in melanoma patients treated with immune checkpoint inhibitors in the COVID-19 era. 在 COVID-19 时代,接受免疫检查点抑制剂治疗的黑色素瘤患者中肌炎和可能的心肌炎增多。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-05 DOI: 10.1007/s00262-024-03803-5
Allison L Gradone, Vincent T Ma, Alexi Vasbinder, Leslie A Fecher, Sarah Yentz, Salim S Hayek, Christopher D Lao

Background: Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy.

Methods: A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis.

Results: 366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%-1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%-1.96%). From November 2019 to December 2021, an additional 246 patients with advanced melanoma were identified. Of these patients, 10 (4.1%, 95% CI 1.97%-7.35%) developed ICI-mediated myocarditis and 10 developed ICI-mediated myositis.

Conclusion: Our study suggests an increase in prevalence of ICI-mediated muscle damage including myositis and myocarditis in the COVID-19 era. Differentiation of these patients and further risk stratification may allow for development of guidelines for nuanced management of this serious complication.

背景:免疫检查点抑制剂(ICI)介导的心肌炎会导致严重的发病率和死亡率。在我们医院,我们注意到 ICI 介导的心肌炎病例的发病率有所上升,因此我们对接受 ICI 治疗的晚期黑色素瘤患者数据库进行了进一步调查:方法:对晚期黑色素瘤患者进行单中心回顾性队列分析,确定ICI介导的心肌炎和肌炎病例:从2014年9月至2019年10月,366名晚期黑色素瘤患者接受了ICI治疗。在这些患者中,ICI介导的心肌炎病例为0例(0%,95% CI 0%-1.0%),ICI介导的肌炎病例为2例(0.55%,95% CI 0.07%-1.96%)。从2019年11月到2021年12月,又发现了246例晚期黑色素瘤患者。在这些患者中,10人(4.1%,95% CI 1.97%-7.35%)发生了ICI介导的心肌炎,10人发生了ICI介导的肌炎:我们的研究表明,在 COVID-19 时代,ICI 介导的肌肉损伤(包括肌炎和心肌炎)的发病率有所上升。对这些患者进行区分并进一步进行风险分层,可为这一严重并发症的精细化管理制定指南。
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引用次数: 0
Antitumor effects of intracranial injection of B7-H3-targeted Car-T and Car-Nk cells in a patient-derived glioblastoma xenograft model. 颅内注射 B7-H3 靶向 Car-T 和 Car-Nk 细胞对患者来源胶质母细胞瘤异种移植模型的抗肿瘤作用。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-05 DOI: 10.1007/s00262-024-03808-0
Tetsuro Tachi, Noriyuki Kijima, Hideki Kuroda, Syunya Ikeda, Koki Murakami, Tomoyoshi Nakagawa, Moto Yaga, Kanji Nakagawa, Reina Utsugi, Ryuichi Hirayama, Yoshiko Okita, Naoki Kagawa, Haruhiko Kishima, Chihaya Imai, Naoki Hosen

Background: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM.

Methods: CAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells.

Results: Both B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts.

Conclusion: Not only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.

背景:多形性胶质母细胞瘤(GBM多形性胶质母细胞瘤(GBM)是最致命的原发性脑肿瘤,需要新型疗法来治疗。最近,嵌合抗原受体(CAR)T 细胞疗法已被证明对 GBM 有效,但它是一种个性化药物,需要高成本和长时间的细胞生产。CAR转化的自然杀伤(NK)细胞可用于 "现成的 "细胞免疫疗法,因为它们不会诱发移植物抗宿主疾病。因此,我们旨在分析以B7-H3为靶点的CAR-T或NK细胞的抗GBM效果,已知B7-H3在GBM中高度表达:方法:使用之前报道的抗 B7-H3 scFv 序列生成靶向 B7-H3 的 CAR-T 细胞。方法:利用之前报道的抗 B7-H3 scFv 序列生成了靶向 B7-H3 的 CAR-T 细胞,同时还生成了转导了 B7-H3 CAR 的脐带血(CB)衍生 NK 细胞。我们在体外分析了它们的抗骨髓肉瘤效果。在患者来源的GBM细胞体内异种移植模型中,研究了颅内注射B7-H3 CAR-T或NK细胞的抗肿瘤效果:结果:B7-H3 CAR-T细胞和CAR-NK细胞在体外对患者来源的GBM细胞均表现出明显的细胞毒性。此外,颅内注射靶向 B7-H3 的 CAR-T 细胞和 CAR-NK 细胞可对患者来源的 GBM 异种移植物产生显著的抗肿瘤效果:结论:不仅是 CAR-T 细胞,源自 CB 的靶向 B7-H3 的 CAR-NK 细胞也可能具有消灭 GBM 细胞的潜力。
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引用次数: 0
Integrative analyses of bulk and single-cell RNA-seq reveals the correlation between SPP1+ macrophages and resistance to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma. 大量和单细胞RNA-seq的整合分析揭示了SPP1+巨噬细胞与食管鳞癌新辅助化疗免疫疗法耐受性之间的相关性。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-05 DOI: 10.1007/s00262-024-03848-6
Zhenyang Geng, Feng Li, Zhichang Yang, Bowen Li, Yifan Xu, Bin Wu, Yinliang Sheng, Ping Yuan, Lan Huang, Yu Qi

Neoadjuvant chemoimmunotherapy (NACI) has significant implications for the treatment of esophageal cancer. However, its clinical efficacy varies considerably among patients, necessitating further investigation into the underlying mechanisms. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology facilitates the analysis of patient heterogeneity at the cellular level, particularly regarding treatment outcomes. In this study, we first analyzed scRNA-seq data of esophageal squamous cell carcinoma (ESCC) following NACI, obtained from the Gene Expression Omnibus (GEO) database. After performing dimensionality reduction, clustering, and annotation on the scRNA-seq data, we employed CellChat to investigate differences in cell-cell communication among samples from distinct efficacy groups. The results indicated that macrophages in the non-responder exhibited stronger cell communication intensity compared to those in responders, with SPP1 and GALECTIN signals showing the most significant differences between the two groups. This finding underscores the crucial role of macrophages in the efficacy of NACI. Subsequently, reclustering of macrophages revealed that Mac-SPP1 may be primarily responsible for treatment resistance, while Mac-C1QC appears to promote T cell activation. Finally, we conducted transcriptome sequencing on ESCC tissues obtained from 32 patients who underwent surgery following NACI. Utilizing CIBERSORT, CIBERSORTx, and WGCNA, we analyzed the heterogeneity of tumor microenvironment among different efficacy groups and validated the correlation between SPP1+ macrophages and resistance to NACI in ESCC using publicly available transcriptome sequencing datasets. These findings suggest that SPP1+ macrophages may represent a key factor contributing to resistance against NACI in ESCC.

新辅助化疗免疫疗法(NACI)对食管癌的治疗具有重要意义。然而,不同患者的临床疗效差异很大,因此有必要进一步研究其潜在机制。单细胞 RNA 测序(scRNA-seq)技术的快速发展有助于在细胞水平分析患者的异质性,尤其是治疗效果。在本研究中,我们首先分析了从基因表达总库(GEO)数据库中获得的食管鳞状细胞癌(ESCC)NACI后的scRNA-seq数据。在对scRNA-seq数据进行降维、聚类和注释后,我们利用CellChat研究了不同疗效组样本之间细胞间通讯的差异。结果表明,与应答者相比,非应答者的巨噬细胞表现出更强的细胞通讯强度,其中 SPP1 和 GALECTIN 信号在两组间的差异最为显著。这一发现强调了巨噬细胞在 NACI 疗效中的关键作用。随后,对巨噬细胞的再聚类发现,Mac-SPP1 可能是治疗耐药性的主要原因,而 Mac-C1QC 似乎促进了 T 细胞的活化。最后,我们对 32 位在 NACI 后接受手术的 ESCC 组织进行了转录组测序。利用CIBERSORT、CIBERSORTx和WGCNA,我们分析了不同疗效组肿瘤微环境的异质性,并利用公开的转录组测序数据集验证了SPP1+巨噬细胞与ESCC对NACI耐药的相关性。这些发现表明,SPP1+巨噬细胞可能是导致ESCC对NACI耐药的一个关键因素。
{"title":"Integrative analyses of bulk and single-cell RNA-seq reveals the correlation between SPP1<sup>+</sup> macrophages and resistance to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma.","authors":"Zhenyang Geng, Feng Li, Zhichang Yang, Bowen Li, Yifan Xu, Bin Wu, Yinliang Sheng, Ping Yuan, Lan Huang, Yu Qi","doi":"10.1007/s00262-024-03848-6","DOIUrl":"10.1007/s00262-024-03848-6","url":null,"abstract":"<p><p>Neoadjuvant chemoimmunotherapy (NACI) has significant implications for the treatment of esophageal cancer. However, its clinical efficacy varies considerably among patients, necessitating further investigation into the underlying mechanisms. The rapid advancement of single-cell RNA sequencing (scRNA-seq) technology facilitates the analysis of patient heterogeneity at the cellular level, particularly regarding treatment outcomes. In this study, we first analyzed scRNA-seq data of esophageal squamous cell carcinoma (ESCC) following NACI, obtained from the Gene Expression Omnibus (GEO) database. After performing dimensionality reduction, clustering, and annotation on the scRNA-seq data, we employed CellChat to investigate differences in cell-cell communication among samples from distinct efficacy groups. The results indicated that macrophages in the non-responder exhibited stronger cell communication intensity compared to those in responders, with SPP1 and GALECTIN signals showing the most significant differences between the two groups. This finding underscores the crucial role of macrophages in the efficacy of NACI. Subsequently, reclustering of macrophages revealed that Mac-SPP1 may be primarily responsible for treatment resistance, while Mac-C1QC appears to promote T cell activation. Finally, we conducted transcriptome sequencing on ESCC tissues obtained from 32 patients who underwent surgery following NACI. Utilizing CIBERSORT, CIBERSORTx, and WGCNA, we analyzed the heterogeneity of tumor microenvironment among different efficacy groups and validated the correlation between SPP1<sup>+</sup> macrophages and resistance to NACI in ESCC using publicly available transcriptome sequencing datasets. These findings suggest that SPP1<sup>+</sup> macrophages may represent a key factor contributing to resistance against NACI in ESCC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11455823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379132","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
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Cancer Immunology, Immunotherapy
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