Clinical & Translational Immunology最新文献

Pretreatment albumin is a prognostic and predictive biomarker for response to atezolizumab across solid tumors 预处理白蛋白是对阿特唑单抗在实体肿瘤中的反应的预后和预测性生物标志物

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-11-08 DOI: 10.1002/cti2.1472

Jonas Saal, Jörg Ellinger, Manuel Ritter, Peter Brossart, Michael Hölzel, Niklas Klümper, Tobias Bald

Objectives

Reliable predictive biomarkers for response to immune checkpoint inhibition (ICI) are lacking. Pretreatment serum albumin, a known prognostic and predictive factor in ICI-treated patients, has been proposed as a potential pharmacokinetic surrogate marker for anti-PD1/PD-L1 antibodies, as it shares a homeostatic pathway with IgG. However, this hypothesis is currently based on theoretical considerations and limited evidence from retrospective data. Therefore, we comprehensively investigated the prognostic and predictive value of pretreatment albumin and its relationship with anti-PD-L1 IgG levels.

Methods

We analysed pretreatment albumin and atezolizumab serum levels and clinical response in four trials (IMvigor210, IMvigor211, IMmotion151 and OAK) of patients with metastatic lung-, renal- or urothelial cancer who received atezolizumab alone or in combination.

Results

A total of 3391 patients were analysed. Correlation between serum albumin and atezolizumab levels was weak (Pearson's coefficient 0.23). We found a strong prognostic value for pretreatment serum albumin across all trials. Both atezolizumab serum levels and serum albumin were independently correlated with overall survival. Importantly, in the three randomised phase III clinical trials, the survival benefit for immunotherapy compared with the active comparator arm was limited to patients with pretreatment serum albumin > 35 g L⁻¹.

Conclusion

Our data do not support the hypothesis that albumin serves as a surrogate for atezolizumab pharmacokinetics. However, we show that albumin on its own exerts strong prognostic value for patients treated with immunotherapy. As benefit from immunotherapy was limited to patients with normal/elevated serum albumin levels, baseline albumin could potentially be used as a predictive marker for immune checkpoint inhibition.

目的缺乏可靠的预测免疫检查点抑制(ICI)反应的生物标志物。预处理血清白蛋白是ici治疗患者的已知预后和预测因素，已被提出作为抗pd1 /PD-L1抗体的潜在药代动力学替代标志物，因为它与IgG共享稳态途径。然而，这一假设目前是基于理论考虑和有限的证据来自回顾性数据。因此，我们全面研究了预处理白蛋白的预后和预测价值及其与抗pd - l1 IgG水平的关系。方法:在4项试验(IMvigor210、IMvigor211、IMmotion151和OAK)中，我们分析了单独或联合使用atezolizumab治疗的转移性肺癌、肾癌或尿路上皮癌患者的预处理白蛋白和atezolizumab血清水平和临床反应。结果共分析3391例患者。血清白蛋白与阿特唑单抗水平的相关性较弱(Pearson系数0.23)。我们发现预处理血清白蛋白在所有试验中具有很强的预后价值。atezolizumab血清水平和血清白蛋白均与总生存期独立相关。重要的是，在三个随机III期临床试验中，与活性对照组相比，免疫治疗的生存获益仅限于预处理血清白蛋白35g L−1的患者。结论:我们的数据不支持白蛋白作为阿特唑单抗药代动力学替代物的假设。然而，我们发现白蛋白本身对接受免疫治疗的患者具有很强的预后价值。由于免疫治疗的益处仅限于血清白蛋白水平正常/升高的患者，因此基线白蛋白可能被用作免疫检查点抑制的预测标志物。

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引用次数: 0

Mass cytometry analysis reveals altered immune profiles in patients with coronary artery disease 质谱分析显示冠状动脉疾病患者的免疫谱发生了改变。

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-11-02 DOI: 10.1002/cti2.1462

Katharine A Kott, Adam S Chan, Stephen T Vernon, Thomas Hansen, Taiyun Kim, Macha de Dreu, Bavani Gunasegaran, Andrew J Murphy, Ellis Patrick, Peter J Psaltis, Stuart M Grieve, Jean Y Yang, Barbara Fazekas de St Groth, Helen M McGuire, Gemma A Figtree

Objective

The importance of inflammation in atherosclerosis is well accepted, but the role of the adaptive immune system is not yet fully understood. To further explore this, we assessed the circulating immune cell profile of patients with coronary artery disease (CAD) to identify discriminatory features by mass cytometry.

Methods

Mass cytometry was performed on patient samples from the BioHEART-CT study, gated to detect 82 distinct cell subsets. CT coronary angiograms were analysed to categorise patients as having CAD (CAD⁺) or having normal coronary arteries (CAD⁻).

Results

The discovery cohort included 117 patients (mean age 61 ± 12 years, 49% female); 79 patients (68%) were CAD⁺. Mass cytometry identified changes in 15 T-cell subsets, with higher numbers of proliferating, highly differentiated and cytotoxic cells and decreases in naïve T cells. Five T-regulatory subsets were related to an age and gender-independent increase in the odds of CAD incidence when expressing CCR2 (OR 1.12), CCR4 (OR 1.08), CD38 and CD45RO (OR 1.13), HLA-DR (OR 1.06) and Ki67 (OR 1.22). Markers of proliferation and differentiation were also increased within B cells, while plasmacytoid dendritic cells were decreased. This combination of changes was assessed using SVM models in discovery and validation cohorts (area under the curve = 0.74 for both), confirming the robust nature of the immune signature detected.

Conclusion

We identified differences within immune subpopulations of CAD⁺ patients which are indicative of a systemic immune response to coronary atherosclerosis. This immune signature needs further study via incorporation into risk scoring tools for the precision diagnosis of CAD.

目的：炎症在动脉粥样硬化中的重要性已被广泛接受，但适应性免疫系统的作用尚不完全清楚。为了进一步探索这一点，我们评估了冠状动脉疾病（CAD）患者的循环免疫细胞图谱，以通过质谱细胞术识别识别特征。方法：对来自BioHEART CT研究的患者样本进行质谱细胞术，门控以检测82个不同的细胞亚群。对CT冠状动脉造影进行分析，将患者分为患有CAD（CAD+）或冠状动脉正常（CAD-）。结果：发现队列包括117名患者（平均年龄61岁 ± 12 女性49%）；79例（68%）为CAD+。大量细胞术检测到15个T细胞亚群发生变化，增殖、高分化和细胞毒性细胞数量增加，幼稚T细胞数量减少。当表达CCR2（OR 1.12）、CCR4（OR 1.08）、CD38和CD45RO（OR 1.13）、HLA-DR（OR 1.06）和Ki67（OR 1.22）时，5个T调节亚群与年龄和性别无关的CAD发病率增加有关。B细胞内增殖和分化标志物也增加，而浆细胞样树突状细胞减少。在发现和验证队列中使用SVM模型评估这种变化组合（曲线下面积 = 两者均为0.74），证实了检测到的免疫特征的鲁棒性。结论：我们发现了CAD+患者免疫亚群的差异，这些差异表明了对冠状动脉粥样硬化的系统免疫反应。这种免疫特征需要进一步研究，将其纳入CAD精确诊断的风险评分工具中。

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引用次数: 0

Early CRP kinetics to predict long-term efficacy of first-line immune-checkpoint inhibition combination therapies in metastatic renal cell carcinoma: an updated multicentre real-world experience applying different CRP kinetics definitions 早期CRP动力学预测转移性肾癌一线免疫检查点抑制联合治疗的长期疗效:应用不同CRP动力学定义的最新多中心真实世界经验

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-10-25 DOI: 10.1002/cti2.1471

Benedikt Hoeh, Cristina Cano Garcia, Severine Banek, Niklas Klümper, Alexander Cox, Jörg Ellinger, Philipp Schmucker, Oliver Hahn, Angelika Mattigk, Friedemann Zengerling, Philippe Becker, Kati Erdmann, Bjoern Thorben Buerk, Luka Flegar, Johannes Huber, Charis Kalogirou, Philip Zeuschner

Objectives

Although biomarkers predicting therapy response in first-line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world first-line mRCC cohort.

Methods

Metastatic renal carcinoma patients treated with IO-based first-line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as ‘CRP flare-responder’, ‘CRP responder’ and ‘non-CRP responder’; according to Ishihara et al., patients were defined as ‘normal’, ‘normalised’ and ‘non-normalised’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses.

Results

Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non-normalised group.

Conclusion

Different early CRP kinetics may predict therapy response in first-line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.

虽然预测一线转移性肾癌(mRCC)治疗反应的生物标志物仍有待确定，但c反应蛋白(CRP)动力学最近与免疫治疗(IO)反应相关。在这里，我们的目的是评估两种当代CRP动力学定义在一个大型、真实的一线mRCC队列中的预测和预后能力。方法回顾性分析5年内接受基于io的一线治疗的转移性肾癌患者。根据Fukuda等人的研究，患者被定义为“CRP反应者”、“CRP反应者”和“非CRP反应者”;根据Ishihara等人的研究，根据患者的早期CRP动力学将其定义为“正常”、“正常化”和“非正常化”。比较患者和肿瘤特征，并通过总生存期(OS)和无进展生存期(PFS)测量治疗结果，包括多变量Cox回归分析。结果在316例mRCC患者中，227例(72%)被分配到CRP组。CRP耀斑(HR [Hazard ratio]: 0.59)和CRP应答者(HR: 0.52)均比非CRP应答者有更长的PFS，但无OS。根据Ishihara的说法，276例(87%)患者被分配到各自的组，与非正常化组相比，正常和正常化患者的PFS和OS都明显更长。结论不同的早期CRP动力学可以预测一线mRCC治疗的疗效。然而，关于最佳的测量时间和频率还需要进一步的研究。

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引用次数: 0

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity 在自身免疫中靶向BMI-1消耗抗体分泌细胞

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-10-04 DOI: 10.1002/cti2.1470

Jack Polmear, Lauren Hailes, Moshe Olshansky, Maureen Rischmueller, Elan L'Estrange-Stranieri, Anne L Fletcher, Margaret L Hibbs, Vanessa L Bryant, Kim L Good-Jacobson

Objectives

B cells drive the production of autoreactive antibody-secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long-term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-1 could deplete ASCs in autoimmune conditions in vivo and in vitro.

Methods

Use of a BMI-1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn^−/− mice, a model of SLE, were treated with the BMI-1 small molecule inhibitor PTC-028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-028 on ASCs derived from Sjögren's syndrome patients was evaluated.

Results

BMI-1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn^−/− mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti-DNA IgG. PTC-028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age-matched healthy donors.

Conclusion

These data provide evidence that inhibiting BMI-1 can deplete ASC in a variety of contexts and thus BMI-1 is a viable therapeutic target for antibody-mediated autoimmune diseases.

在系统性红斑狼疮(SLE)和Sjögren综合征等自身免疫性疾病中，B细胞驱动自身反应性抗体分泌细胞(ASCs)的产生，导致长期器官损伤。目前针对抗体介导的自身免疫性疾病的治疗是靶向B细胞或广泛抑制免疫系统。然而，先前存在的长寿命ASCs通常难以治疗，留下了一个自身反应性细胞库，继续产生抗体。因此，开发针对ASCs的新型治疗方法对于改善患者预后至关重要。我们的目的是测试靶向表观遗传调节剂BMI-1是否可以在体内和体外的自身免疫性疾病中消耗ASCs。方法研究BMI-1抑制剂在小鼠和人自身免疫性疾病中的应用。在评估ASCs、血清抗体和免疫复合物之前，用BMI-1小分子抑制剂PTC-028治疗SLE模型Lyn - / -小鼠。为了检测人类ASC的存活，建立了一种新的基于人成纤维细胞的检测方法，并评估了PTC-028对Sjögren综合征患者ASC的影响。结果抑制BMI-1可显著降低Lyn - / -小鼠脾和骨髓ASCs。ASCs的下降与细胞周期基因表达异常有关，并导致血清IgG3、免疫复合物和抗dna IgG的显著下降。PTC-028在降低Sjögren综合征患者和年龄匹配的健康供体的离体浆细胞存活率方面也有效。结论这些数据表明，抑制BMI-1可在多种情况下消耗ASC，因此BMI-1是抗体介导的自身免疫性疾病的可行治疗靶点。

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引用次数: 0

Dopaminergic regulation of inflammation and immunity in Parkinson's disease: friend or foe? 帕金森病炎症和免疫的多巴胺能调节：朋友还是敌人？

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-09-29 DOI: 10.1002/cti2.1469

Alessia Furgiuele, Frederico C Pereira, Stefano Martini, Franca Marino, Marco Cosentino

Parkinson's disease (PD) is a neurodegenerative disease affecting 7–10 million people worldwide. Currently, there is no treatment available to prevent or delay PD progression, partially due to the limited understanding of the pathological events which lead to the death of dopaminergic neurons in the substantia nigra in the brain, which is known to be the cause of PD symptoms. The current available treatments aim at compensating dopamine (DA) deficiency in the brain using its precursor levodopa, dopaminergic agonists and some indirect dopaminergic agents. The immune system is emerging as a critical player in PD. Therefore, immune-based approaches have recently been proposed to be used as potential antiparkinsonian agents. It has been well-known that dopaminergic pathways play a significant role in regulating immune responses in the brain. Although dopaminergic agents are the primary antiparkinsonian treatments, their immune regulatory effect has yet to be fully understood. The present review summarises the current available evidence of the immune regulatory effects of DA and its mimics and discusses dopaminergic agents as antiparkinsonian drugs. Based on the current understanding of their involvement in the regulation of neuroinflammation in PD, we propose that targeting immune pathways involved in PD pathology could offer a better treatment outcome for PD patients.

帕金森病（PD）是一种神经退行性疾病，影响全球700万至1000万人。目前，还没有可用的治疗方法来预防或延迟帕金森病的进展，部分原因是对导致大脑黑质多巴胺能神经元死亡的病理事件了解有限，这是已知的帕金森病症状的原因。目前可用的治疗方法旨在使用其前体左旋多巴、多巴胺能激动剂和一些间接多巴胺能药物来补偿大脑中的多巴胺（DA）缺乏。免疫系统正在成为帕金森病的关键参与者。因此，最近有人提出将基于免疫的方法用作潜在的抗帕金森病药物。众所周知，多巴胺能通路在调节大脑免疫反应中发挥着重要作用。尽管多巴胺能药物是主要的抗帕金森病治疗方法，但其免疫调节作用尚待充分了解。本综述总结了DA及其模拟物免疫调节作用的现有证据，并讨论了多巴胺能药物作为抗帕金森病药物的作用。基于目前对它们参与PD神经炎症调节的理解，我们提出靶向参与PD病理的免疫途径可以为PD患者提供更好的治疗结果。

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引用次数: 0

Autoimmune uveitis in Behçet's disease and Vogt-Koyanagi-Harada disease differ in tissue immune infiltration and T cell clonality behet病和Vogt-Koyanagi-Harada病的自身免疫性葡萄膜炎在组织免疫浸润和T细胞克隆方面存在差异

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-09-15 DOI: 10.1002/cti2.1461

Hao Kang, Hongjian Sun, Yang Yang, Zewen K Tuong, Minglei Shu, Yunbo Wei, Yu Zhang, Di Yu, Yong Tao

Objectives

Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet's disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD can show similar clinical manifestations, but the underlying immunopathogenesis remains unclear.

Methods

To understand immune landscapes in inflammatory eye tissues, we performed single-cell RNA paired with T cell receptor (TCR) sequencing of immune cell infiltrates in aqueous humour from six patients with BD (N = 3) and VKHD (N = 3) uveitis patients.

Results

Although T cells strongly infiltrated in both types of autoimmune uveitis, myeloid cells only significantly presented in BD uveitis but not in VKHD uveitis. Conversely, VKHD uveitis but not BD uveitis showed an overwhelming dominance by CD4⁺ T cells (> 80%) within the T cell population due to expansion of CD4⁺ T cell clusters with effector memory (Tem) phenotypes. Correspondingly, VKHD uveitis demonstrated a selective expansion of CD4⁺ T cell clones which were enriched in pro-inflammatory Granzyme H⁺ CD4⁺ Tem cluster and showed TCR and Th1 pathway activation. In contrast, BD uveitis showed a preferential expansion of CD8⁺ T cell clones in pro-inflammatory Granzyme H⁺ CD8⁺ Tem cluster, and pathway activation for cytoskeleton remodelling, cellular adhesion and cytotoxicity.

Conclusion

Single-cell analyses of ocular tissues reveal distinct landscapes of immune cell infiltration and T-cell clonal expansions between VKHD and BD uveitis. Preferential involvements of pro-inflammatory CD4⁺ Th1 cells in VKHD and cytotoxic CD8⁺ T cells in BD suggest a difference in disease immunopathogenesis and can guide precision disease management.

非感染性葡萄膜炎通常继发于全身性自身免疫性疾病，其中behet病(BD)和Vogt-Koyanagi-Harada病(VKHD)是两种最常见的原因。葡萄膜炎在BD和VKHD中可以表现出相似的临床表现，但潜在的免疫发病机制尚不清楚。方法对6例BD (N = 3)和VKHD (N = 3)葡萄膜炎患者房水中浸润的免疫细胞进行单细胞RNA配对T细胞受体(TCR)测序，以了解炎症性眼组织的免疫景观。结果两种自身免疫性葡萄膜炎均有T细胞浸润，但髓样细胞仅在BD型葡萄膜炎中有明显浸润，在VKHD型葡萄膜炎中无明显浸润。相反，由于具有效应记忆(Tem)表型的CD4+ T细胞簇的扩增，VKHD葡萄膜炎而非BD葡萄膜炎在T细胞群中显示出CD4+ T细胞的压倒性优势(> 80%)。相应地，VKHD葡萄膜炎表现出CD4+ T细胞克隆的选择性扩增，这些克隆富集促炎颗粒酶H+ CD4+ Tem簇，并表现出TCR和Th1途径的激活。相比之下，BD葡萄膜炎表现出促炎颗粒酶H+ CD8+ Tem簇中CD8+ T细胞克隆的优先扩增，以及细胞骨架重塑、细胞粘附和细胞毒性的途径激活。结论眼组织单细胞分析显示VKHD和BD葡萄膜炎在免疫细胞浸润和t细胞克隆扩增方面存在明显差异。促炎CD4+ Th1细胞优先参与VKHD，细胞毒性CD8+ T细胞优先参与BD，提示疾病免疫发病机制的差异，可以指导精确的疾病管理。

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引用次数: 0

Individualised adjuvant immunotherapy with neoantigen-reactive T cells for gastric signet-ring cell carcinoma 新抗原反应性T细胞个体化辅助免疫治疗胃印戒细胞癌

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-09-11 DOI: 10.1002/cti2.1467

Naiqing Ding, Qin Liu, Juan Du, Jie Shao, Yang Yang, Ju Yang, Fangjun Chen, Lixia Yu, Baorui Liu, Jia Wei

Objectives

The signet-ring cell carcinoma (SRCC) of the stomach is highly invasive. Patients with stage III gastric SRCC usually experience tumor recurrence within 2 years after radical surgery. Unfortunately, there is no effective treatment to postpone recurrence following adjuvant chemotherapy. Our study aimed to explore the safety and efficacy of neoantigen-reactive T lymphocytes (NRTs) in patients with stage III gastric SRCC.

Methods

The study included 20 patients with stage III gastric SRCC who received radical surgery and adjuvant chemotherapy. Following the adjuvant chemotherapy, they underwent treatment with a range of one to four cycles of personalised neoantigen-reactive T cells. The primary endpoint was the median progression-free survival (mDFS). The secondary endpoint was safety and immune responses. The median duration of follow-up was 41 months (95% CI: 39–42.9 months).

Results

Our results showed that patients who received adjuvant neoantigen-reactive T-cell immunotherapy demonstrated a propensity towards prolonged disease-free survival (DFS) and overall survival (OS) in comparison to previous studies. The 2-year DFS and OS rates reached 73.7% and 95%, respectively, whereas the 5-year DFS and OS rates were 44% and 69%. The median DFS was 41 months (95% CI: 28.9–53.1 months) and the median OS was not reached. In addition, there was a significant increase in serum concentrations of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ after cell immunotherapy. The adverse reactions were mild.

Conclusion

In conclusion, adjuvant immunotherapy with NRTs showed promising efficacy alongside a manageable safety profile.

目的胃印戒细胞癌(SRCC)具有高度侵袭性。III期胃小细胞癌患者通常在根治性手术后2年内肿瘤复发。不幸的是，没有有效的治疗方法来延缓辅助化疗后的复发。我们的研究旨在探讨新抗原反应性T淋巴细胞(nrt)在III期胃SRCC患者中的安全性和有效性。方法对20例接受根治性手术和辅助化疗的III期胃小细胞癌患者进行研究。在辅助化疗之后，他们接受了一到四个周期的个体化新抗原反应性T细胞治疗。主要终点是中位无进展生存期(mDFS)。次要终点是安全性和免疫反应。中位随访时间为41个月(95% CI: 39-42.9个月)。我们的研究结果显示，与之前的研究相比，接受辅助新抗原反应性t细胞免疫治疗的患者表现出延长无病生存期(DFS)和总生存期(OS)的倾向。2年DFS和OS分别达到73.7%和95%，而5年DFS和OS分别为44%和69%。中位DFS为41个月(95% CI: 28.9-53.1个月)，中位OS未达到。此外，细胞免疫治疗后血清IL-2、IL-4、IL-6、IL-10、TNF-α和IFN-γ浓度均显著升高。不良反应轻微。综上所述，nrt辅助免疫治疗具有良好的疗效和可控的安全性。

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引用次数: 0

Design, optimisation and standardisation of a high-dimensional spectral flow cytometry workflow assessing T-cell immunophenotype in patients with melanoma 设计、优化和标准化评估黑色素瘤患者t细胞免疫表型的高维光谱流式细胞术工作流程

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-09-07 DOI: 10.1002/cti2.1466

Jack M Edwards, Miles C Andrews, Hayley Burridge, Robin Smith, Carole Owens, Mark Edinger, Katherine Pilkington, Juliette Desfrancois, Mark Shackleton, Sashendra Senthi, Menno C van Zelm

Objectives

Despite the success of immune checkpoint blockade, most metastatic melanoma patients fail to respond to therapy or experience severe toxicity. Assessment of biomarkers and immunophenotypes before or early into treatment will help to understand favourable responses and improve therapeutic outcomes.

Methods

We present a high-dimensional approach for blood T-cell profiling using three multi-parameter cytometry panels: (1) a TruCount panel for absolute cell counts, (2) a 27-colour spectral panel assessing T-cell markers and (3) a 20-colour spectral panel evaluating intracellular cytokine expression. Pre-treatment blood mononuclear cells from patients and healthy controls were cryopreserved before staining across 11 batches. Batch effects were tracked using a single-donor control and the suitability of normalisation was assessed. The data were analysed using manual gating and high-dimensional strategies.

Results

Batch-to-batch variation was minimal, as demonstrated by the dimensionality reduction of batch-control samples, and normalisation did not improve manual or high-dimensional analysis. Application of the workflow demonstrated the capacity of the panels and showed that patients had fewer lymphocytes than controls (P = 0.0027), due to lower naive CD4⁺ (P = 0.015) and CD8⁺ (P = 0.011) T cells and follicular helper T cells (P = 0.00076). Patients showed trends for higher proportions of Ki67 and IL-2-expressing cells within CD4⁺ and CD8⁺ memory subsets, and increased CD57 and EOMES expression within TCRγδ⁺ T cells.

Conclusion

Our optimised high-parameter spectral cytometry approach provided in-depth profiling of blood T cells and found differences in patient immunophenotype at baseline. The robustness of our workflow, as demonstrated by minimal batch effects, makes this approach highly suitable for the longitudinal evaluation of immunotherapy effects.

尽管免疫检查点阻断疗法取得了成功，但大多数转移性黑色素瘤患者对治疗没有反应或出现严重的毒性。在治疗前或早期评估生物标志物和免疫表型将有助于了解有利的反应并改善治疗结果。我们提出了一种高维的血液t细胞分析方法，使用三种多参数细胞计数面板:(1)用于绝对细胞计数的TruCount面板，(2)评估t细胞标记的27色光谱面板，(3)评估细胞内细胞因子表达的20色光谱面板。在11批染色前，冷冻保存患者和健康对照的治疗前血液单个核细胞。使用单供体对照跟踪批处理效果，并评估归一化的适用性。采用人工门控和高维策略对数据进行分析。结果批与批之间的差异是最小的，正如批控制样本的维数降低所证明的那样，标准化并没有改善人工或高维分析。工作流程的应用证明了面板的容量，并显示患者的淋巴细胞比对照组少(P = 0.0027)，这是由于初始CD4+ (P = 0.015)和CD8+ (P = 0.011) T细胞和滤泡辅助T细胞(P = 0.00076)较低。患者表现出CD4+和CD8+记忆亚群中Ki67和il -2表达细胞比例升高的趋势，TCRγδ+ T细胞中CD57和EOMES表达增加。我们优化的高参数光谱细胞术方法提供了深入的血液T细胞图谱，并发现了基线时患者免疫表型的差异。我们工作流程的稳健性，正如最小批量效应所证明的那样，使得这种方法非常适合免疫治疗效果的纵向评估。

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引用次数: 0

Genomic and tumour microenvironmental biomarkers of immune checkpoint inhibitor response in advanced Taiwanese melanoma 台湾晚期黑色素瘤中免疫检查点抑制剂反应的基因组和肿瘤微环境生物标志物

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-08-29 DOI: 10.1002/cti2.1465

John Wen-Cheng Chang, Chien-Jung Huang, Wen-Kuan Huang, Yu-Chao Wang, Jia-Juan Hsieh, Yao-Yu Chang, Yen-Lin Huang, Chia-Ling Wu, Yeh-Han Wang, Shu-Jen Chen, Kien Thiam Tan, Chiao-Ping Chen, Chiao-En Wu

Objective

Genomic biomarkers predicting immune checkpoint inhibitor (ICI) treatment outcomes for Asian metastatic melanoma have been rarely reported. This study presents data on next-generation sequencing (NGS) and tumour microenvironment biomarkers in 33 cases.

Methods

Thirty-three patients with advanced melanoma, who underwent ICI treatment at the Chang Gung Memorial Hospital in Taiwan, were recruited. The study evaluated clinical outcomes, including response rate, disease control rate, progression-free survival (PFS) rate and overall survival (OS) rate. Archived tissue samples from 33 cases were subjected to NGS by ACTOnco, and ACTTME was employed in 25 cases.

Results

The most prevalent driver mutations were BRAF mutations (24.2%), followed by NRAS (15.2%), KIT (12.1%), KRAS (9.1%) and NF1 (9.1%) mutations. Acral/mucosal melanomas exhibited distinct mutation patterns compared to non-acral melanomas. Tumour mutational burden estimated using ACTOnco was not associated with ICI efficacy. Notably, genetic alterations in the p53 pathway (CDKNA2 loss, MDM2 gain/amplification and TP53 mutation) accounted for 36.4% and were significantly associated with unfavourable PFS (median PFS 2.7 months vs. 3.9 months, P = 0.0394). Moreover, 26 genes were identified as differentially expressed genes that were upregulated in patients with clinical benefits compared to those without benefits. Four genes, GZMH, GZMK, AIM2 and CTLA4, were found to be associated with both PFS and OS.

Conclusion

Genetic alterations in the p53 pathway may be critical in Asian patients with melanoma undergoing ICI treatment. Further investigation is required to explore this mechanism and validate these findings.

目的预测免疫检查点抑制剂(ICI)治疗亚洲转移性黑色素瘤预后的基因组生物标志物很少被报道。本研究报告了33例患者的新一代测序(NGS)和肿瘤微环境生物标志物的数据。方法选取33例在台湾长庚纪念医院接受ICI治疗的晚期黑色素瘤患者。该研究评估了临床结果，包括缓解率、疾病控制率、无进展生存(PFS)率和总生存(OS)率。33例组织标本采用ACTOnco进行NGS, 25例采用ACTTME。结果BRAF突变最多(24.2%)，其次是NRAS(15.2%)、KIT(12.1%)、KRAS(9.1%)和NF1(9.1%)。与非肢端黑色素瘤相比，肢端/粘膜黑色素瘤表现出不同的突变模式。使用ACTOnco估计的肿瘤突变负荷与ICI疗效无关。值得注意的是，p53通路的遗传改变(CDKNA2缺失、MDM2获得/扩增和TP53突变)占36.4%，与不利的PFS显著相关(中位PFS为2.7个月vs. 3.9个月，P = 0.0394)。此外，26个基因被鉴定为差异表达基因，与那些没有临床获益的患者相比，这些基因在临床获益的患者中表达上调。GZMH、GZMK、AIM2和CTLA4四个基因与PFS和OS均相关。结论p53通路的基因改变可能在接受ICI治疗的亚洲黑色素瘤患者中起关键作用。需要进一步的研究来探索这一机制并验证这些发现。

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引用次数: 0

Glucocorticoid regulation of the mTORC1 pathway modulates CD4+ T cell responses during infection 糖皮质激素调节mTORC1通路在感染期间调节CD4+ T细胞反应

IF 5.8 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology

Pub Date : 2023-08-29 DOI: 10.1002/cti2.1464

Huihui Chen, Zhiwen Liu, Jie Zha, Li Zeng, Runyan Tang, Chengyuan Tang, Juan Cai, Chongqing Tan, Hong Liu, Zheng Dong, Guochun Chen

Objectives

Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4⁺ T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4⁺ T cells during infection.

Methods

We consistently measured FOXP3, inflammatory cytokines and phospho-S6 ribosomal protein levels in CD4⁺ T cells from patients undergoing conventional GC treatment. Using Foxp3^EGFP animals, we investigated the dynamic activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4⁺ T cells under the influence of GCs.

Results

GCs dynamically altered the expression pattern of FOXP3 in CD4⁺ T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4⁺ T cells. Dynamic activation of the mTORC1 signaling modified the GC-dampened immunoregulatory capacity of CD4⁺ T cells by phenotypically and functionally bolstering the FOXP3⁺ Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC-dampened immunoregulatory capacity of CD4⁺ T cells.

Conclusion

These findings highlight a novel mTORC1-mediated mechanism underlying CD4⁺ T cell immunity in the context of conventional GC treatment.

传统的糖皮质激素(GC)治疗由于其对CD4+ T细胞的抑制作用而具有明显的机会性感染风险。本研究旨在探讨GCs在感染期间调节CD4+ T细胞功能的机制。方法连续测定常规GC治疗患者CD4+ T细胞中FOXP3、炎性细胞因子和磷酸化- s6核糖体蛋白水平。我们利用Foxp3EGFP动物，研究了GCs影响下雷帕霉素复合物1 (mTORC1)通路的机制靶点的动态激活及其与CD4+ T细胞免疫调节功能的相关性。结果GCs动态改变了FOXP3在CD4+ T细胞中的表达模式，促进其在刺激下获得活性T调节性(Treg)细胞表型。在机制上，GCs破坏了mTORC1通路的动力学，这与CD4+ T细胞的表型转化和功能特性密切相关。mTORC1信号的动态激活通过表型和功能上增强FOXP3+ Treg细胞来修饰gc抑制的CD4+ T细胞的免疫调节能力。靶向mTORC1通路的干预有效地调节了gc抑制的CD4+ T细胞的免疫调节能力。这些发现强调了在常规GC治疗背景下，mtorc1介导的CD4+ T细胞免疫的新机制。

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引用次数: 0