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Response to Chemoimmunotherapy Is Associated With Expansion of Systemic Antitumor CD4 + Th1 Response in Metastatic Non-Small Cell Lung Cancer. 转移性非小细胞肺癌对化学免疫治疗的反应与全身抗肿瘤CD4 + Th1反应的扩大有关
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-09-01 DOI: 10.1097/CJI.0000000000000454
Mylène Wespiser, Amélie Marguier, Benoît Lecoester, Thibault Richard, Laura Boullerot, Marine Malfroy, Abhishek Kumar, Caroline Laheurte, Olivier Adotévi

Limited data have reported the evolution of antitumor immune responses under chemoimmunotherapy (chemo-IO) in patients with metastatic non-small cell lung cancer. In this concise study, we performed dynamic monitoring of antitumor CD4 + T helper 1 (Th1) response in peripheral blood from 12 patients receiving a first-line chemo-IO. Tumor-reactive CD4 + Th1 cells were assessed within blood lymphocytes using interferon-gamma enzyme-linked immunospot assay to detect telomerase (TERT)-specific T cells at baseline, 3 and 12 months after treatment. An induction of circulating anti-TERT CD4 + Th1 response were found in 6 of 12 patients at 3 months after chemo-IO. In contrast, 3 patients had a substantial decrease in their preexisting response and 3 remained nonimmune responders. Among patients with chemo-IO-induced immune response, half achieved an objective clinical response and had long-lasting circulating anti-TERT CD4 + Th1 cells detected for at least 1 year. In contrast, no objective response was documented in nonimmune responders and a link between the loss of anti-TERT CD4 + Th1 responses were observed in patients with progressive disease. This preliminary work supports a relationship between the efficacy of combinatorial chemo-IO and circulating anti-TERT CD4 + Th1 responses and highlights the interest to implement blood-based monitoring of tumor-reactive CD4 + T cells that could be additional help for patient management.

有限的数据报道了转移性非小细胞肺癌患者化疗免疫治疗(chemo-IO)下抗肿瘤免疫反应的演变。在这项简明的研究中,我们对12名接受一线化疗的患者外周血中的抗肿瘤CD4 + T辅助1 (Th1)反应进行了动态监测。在基线、治疗后3个月和12个月,使用干扰素- γ酶联免疫斑点法检测端粒酶(TERT)特异性T细胞,评估血液淋巴细胞中肿瘤反应性CD4 + Th1细胞。化疗后3个月,12例患者中有6例出现循环抗tert CD4 + Th1反应。相比之下,3名患者先前存在的反应明显减少,3名患者仍然没有免疫反应。在化疗诱导免疫反应的患者中,有一半达到了客观临床反应,并且在至少1年内检测到持久的循环抗tert CD4 + Th1细胞。相比之下,在非免疫应答者中没有客观的应答记录,并且在进行性疾病患者中观察到抗tert CD4 + Th1应答的丧失之间的联系。这项初步工作支持了组合化疗- io和循环抗tert CD4 + Th1反应之间的关系,并强调了实施基于血液的肿瘤反应性CD4 + T细胞监测的兴趣,这可能为患者管理提供额外的帮助。
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引用次数: 3
Brief Communication: Lambert-Eaton Myasthenic Paraneoplastic Syndrome Associated With Merkel Cell Carcinoma Successfully Treated by Immune Checkpoint Inhibitors: 2 Cases. 简短交流:免疫检查点抑制剂成功治疗与默克尔细胞癌相关的Lambert-Eaton肌无力副肿瘤综合征2例。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-09-01 DOI: 10.1097/CJI.0000000000000480
Marion Gra, Anne Pham-Ledard, Emilie Gerard, Caroline Dutriaux, Marie Beylot-Barry, Fanny Duval, Louis Carla, Antoine Soulages, Sorilla Prey

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous tumor with high metastatic potential. In rare cases, it can be associated with paraneoplastic syndromes (PNS), which result from an antitumor immunity against antigens produced by the tumor itself. Lambert-Eaton Myasthenic Syndrome (LEMS) is a neurological autoimmune PNS characterized by an impairment of the neuromuscular junction, leading to proximal muscle weakness and fatigability. Although the development of immune checkpoint inhibitors (ICI) is a breakthrough in the management of many cancers, onset or worsen of immune diseases has been described. Thereby, in patients with previous neurological PNS like LEMS, the ICI therapy for cancer may aggravate neurological symptoms and lead to irreversible impairment. We report here 2 cases of patients with metastatic MCC associated with a LEMS at the diagnosis. Both successfully received ICI therapies (anti-PDL1 avelumab and anti-PD1 pembrolizumab) without worsening of LEMS and any major immune-related adverse effects. Their neurological condition improved and disappeared concomitantly with the efficacy of immunotherapy, and we did not observe relapse of both MCC and LEMS after treatment discontinuation. Finally, we performed a complete review of the literature, which confirmed that ICI treatment could be discussed for patients with paraneoplastic LEMS, and emphasized the need for multidisciplinary management.

默克尔细胞癌(MCC)是一种侵袭性神经内分泌皮肤肿瘤,具有高转移潜力。在极少数情况下,它可能与副肿瘤综合征(PNS)有关,这是由于对肿瘤本身产生的抗原的抗肿瘤免疫所致。Lambert-Eaton肌无力综合征(LEMS)是一种神经自身免疫性PNS,其特征是神经肌肉连接处受损,导致近端肌肉无力和疲劳。尽管免疫检查点抑制剂(ICI)的发展是许多癌症治疗的突破,但免疫疾病的发病或恶化已被描述。因此,在既往有LEMS等神经性PNS的患者中,癌症的ICI治疗可能加重神经系统症状并导致不可逆的损害。我们在此报告2例转移性MCC患者在诊断时伴有LEMS。两人都成功接受了ICI治疗(抗pdl1 avelumab和抗pd1 pembrolizumab),没有LEMS恶化和任何主要的免疫相关不良反应。随着免疫治疗的效果,他们的神经系统状况得到改善和消失,我们没有观察到停药后MCC和LEMS的复发。最后,我们对文献进行了完整的回顾,证实了可以讨论副肿瘤LEMS患者的ICI治疗,并强调了多学科管理的必要性。
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引用次数: 0
Efficacy and Safety Profile of PD-1 Inhibitors Versus Chemotherapy in the Second-Line Treatment of Advanced Esophageal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PD-1抑制剂与化疗在晚期食管鳞状细胞癌二线治疗中的疗效和安全性:随机对照试验的系统评价和荟萃分析
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-09-01 DOI: 10.1097/CJI.0000000000000479
Zhao Jin, Minghe Zhao

Programmed death 1 (PD-1) inhibitors have emerged as the new standard of care for the second-line treatment of advanced esophageal squamous cell carcinoma. There have been lots of research lately concerning the topic. A comprehensive assessment of the efficacy and safety profile between PD-1 inhibitors and chemotherapy is warranted. Hence, we carried out a systematic review and meta-analysis to illustrate this issue. Pubmed, Embase, Cochrane Library, and Embase were searched systematically until May 1, 2022. We extracted data on efficacy and safety and calculated the pooled hazard ratios (HRs) and relative ratios (RRs) with 95% CI using randomized-effect or fixed-effect models. A subgroup analysis was applied to explore the factors modifying the response to PD-1 inhibitors. Ultimately, a total of 5 studies involving 1970 patients were included in our meta-analysis. PD-1 inhibitors group could attain greater overall survival (OS) benefit (HR = 0.73, 95% CI: 0.66-0.81, P < 0.001) and nearly favorable progression-free survival (HR = 0.89, 0.76-1.04, P = 0.13). Treatment-related adverse events (RR = 0.76, 95% CI: 0.64-0.91, P = 0.004) and level 3-5 treatment-related adverse events (RR = 0.40, 95% CI: 0.32-0.49, P < 0.001) were significantly diminished in PD-1 inhibitors groups. Among all modifying factors, programmed death ligand 1 combined positive score was positively associated with the patient's OS. The analysis suggests that PD-1 inhibitors exhibited better survival outcomes and safety profiles than standard-of-care chemotherapy. High levels of programmed death ligand 1 combined positive scores were associated with an enhanced response to PD-1 immunotherapies concerning OS.

程序性死亡1 (PD-1)抑制剂已成为晚期食管鳞状细胞癌二线治疗的新标准。最近有很多关于这个话题的研究。有必要对PD-1抑制剂和化疗之间的疗效和安全性进行全面评估。因此,我们进行了系统回顾和荟萃分析来说明这个问题。系统检索Pubmed, Embase, Cochrane Library和Embase,直到2022年5月1日。我们提取了疗效和安全性的数据,并使用随机效应或固定效应模型计算了95% CI的合并风险比(hr)和相对比(RRs)。采用亚组分析探讨影响PD-1抑制剂疗效的因素。最终,我们的荟萃分析共纳入了5项涉及1970例患者的研究。PD-1抑制剂组可获得更大的总生存期(OS)获益(HR = 0.73, 95% CI: 0.66-0.81, P < 0.001)和接近有利的无进展生存期(HR = 0.89, 0.76-1.04, P = 0.13)。PD-1抑制剂组治疗相关不良事件(RR = 0.76, 95% CI: 0.64-0.91, P = 0.004)和3-5级治疗相关不良事件(RR = 0.40, 95% CI: 0.32-0.49, P < 0.001)显著减少。在所有修饰因子中,程序性死亡配体1联合阳性评分与患者OS呈正相关。分析表明,PD-1抑制剂比标准治疗化疗具有更好的生存结果和安全性。高水平的程序性死亡配体1联合阳性评分与PD-1免疫疗法对OS的增强反应相关。
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引用次数: 0
Biologically Interpretable Deep Learning To Predict Response to Immunotherapy In Advanced Melanoma Using Mutations and Copy Number Variations. 利用突变和拷贝数变异,生物学上可解释的深度学习预测晚期黑色素瘤免疫治疗的反应。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-07-01 DOI: 10.1097/CJI.0000000000000475
Liuchao Zhang, Lei Cao, Shuang Li, Liuying Wang, Yongzhen Song, Yue Huang, Zhenyi Xu, Jia He, Meng Wang, Kang Li

Only 30-40% of advanced melanoma patients respond effectively to immunotherapy in clinical practice, so it is necessary to accurately identify the response of patients to immunotherapy pre-clinically. Here, we develop KP-NET, a deep learning model that is sparse on KEGG pathways, and combine it with transfer- learning to accurately predict the response of advanced melanomas to immunotherapy using KEGG pathway-level information enriched from gene mutation and copy number variation data. The KP-NET demonstrates best performance with AUROC of 0.886 on testing set and 0.803 on an unseen evaluation set when predicting responders (CR/PR/SD with PFS ≥6 mo) versus non-responders (PD/SD with PFS <6 mo) in anti-CTLA-4 treated melanoma patients. The model also achieves an AUROC of 0.917 and 0.833 in predicting CR/PR versus PD, respectively. Meanwhile, the AUROC is 0.913 when predicting responders versus non-responders in anti-PD-1/PD-L1 melanomas. Moreover, the KP-NET reveals some genes and pathways associated with response to anti-CTLA-4 treatment, such as genes PIK3CA, AOX1 and CBLB, and ErbB signaling pathway, T cell receptor signaling pathway, et al. In conclusion, the KP-NET can accurately predict the response of melanomas to immunotherapy and screen related biomarkers pre-clinically, which can contribute to precision medicine of melanoma.

在临床实践中,只有30-40%的晚期黑色素瘤患者对免疫治疗有效,因此有必要在临床前准确识别患者对免疫治疗的反应。在这里,我们开发了KP-NET,这是一种深度学习模型,它在KEGG通路上是稀疏的,并将其与迁移学习相结合,利用丰富的基因突变和拷贝数变异数据的KEGG通路水平信息,准确预测晚期黑色素瘤对免疫治疗的反应。在预测反应者(PFS≥6个月的CR/PR/SD)与无反应者(PFS的PD/SD)相比,KP-NET在测试集上的AUROC为0.886,在未知评估集上的AUROC为0.803
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引用次数: 1
Fecal Microbiota Transplantation for Immune Checkpoint Inhibitor-Induced Colitis Is Safe and Contributes to Recovery: Two Case Reports. 粪便微生物群移植治疗免疫检查点抑制剂诱导的结肠炎是安全的,并有助于恢复:两例报告
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-07-01 DOI: 10.1097/CJI.0000000000000474
Bas Groenewegen, Elisabeth M Terveer, Arjen Joosse, Marieke C Barnhoorn, Romy D Zwittink

Immune checkpoint inhibitors (ICIs) have improved the prognosis in multiple cancer types. However, ICIs can induce immune-related adverse events such as immune-mediated enterocolitis (IMC). The gut microbiota may be implicated in IMC development. Therefore, we investigated fecal microbiota transplantation (FMT) as a treatment option for 2 patients with metastatic cancer suffering from refractory IMC. The patients were treated with, respectively, 1 and 3 FMTs after vancomycin pre-treatment. We monitored defecation frequency, fecal calprotectin, and microbiota composition. After FMT, both patients improved in defecation frequency, were discharged from the hospital, and received lower dosage of immunosuppressive therapy. Patient 1 developed an invasive pulmonary aspergillosis deemed to be related to prolonged steroid exposure. Patient 2 suffered from a Campylobacter jejuni infection after the first FMT and was treated with meropenem, resulting in a low-diversity microbiota profile and increased calprotectin levels and defecation frequency. After a second and third FMT, bacterial diversity increased and defecation frequency and calprotectin levels decreased. Pre-FMT, both patients showed low bacterial richness, but varying bacterial diversity. After FMT, diversity and richness were similar to healthy donor levels. In conclusion, FMT resulted in improvement of IMC symptoms and corresponding microbial changes in 2 cancer patients with refractory IMC. While more research is warranted, microbiome-modulation could be a promising new therapeutic option for IMC.

免疫检查点抑制剂(ICIs)改善了多种癌症类型的预后。然而,ICIs可诱导免疫相关不良事件,如免疫介导性小肠结肠炎(IMC)。肠道微生物群可能与IMC的发展有关。因此,我们研究了粪便微生物群移植(FMT)作为2例转移性癌症合并难治性IMC的治疗选择。在万古霉素预处理后,患者分别接受1次和3次fmt治疗。我们监测排便频率、粪钙保护蛋白和微生物群组成。经FMT治疗后,两例患者排便次数均有所改善,出院,并接受较低剂量的免疫抑制治疗。患者1发生侵袭性肺曲霉病,认为与长期使用类固醇有关。患者2在第一次FMT后出现空肠弯曲杆菌感染,并使用美罗培南治疗,导致微生物群多样性低,钙保护蛋白水平升高和排便频率增加。在第二次和第三次FMT后,细菌多样性增加,排便频率和钙保护蛋白水平下降。fmt前,两例患者均显示细菌丰富度低,但细菌多样性不同。FMT后,多样性和丰富度与健康供体水平相似。综上所述,FMT改善了2例难治性IMC患者的IMC症状和相应的微生物变化。虽然需要进行更多的研究,但微生物组调节可能是一种有希望的治疗IMC的新选择。
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引用次数: 0
Validating a Macrophage Marker Gene Signature (MMGS) in Lung Adenocarcinoma Prognosis and Response to Immunotherapy. 巨噬细胞标记基因标记(MMGS)在肺腺癌预后和免疫治疗反应中的作用。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-07-01 DOI: 10.1097/CJI.0000000000000477
Peng Song, Dilinaer Wusiman, Wenbin Li, Lei Guo, Jianming Ying, Shugeng Gao, Jie He

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide. Tumor-associated macrophages play pivotal roles in the tumor microenvironment (TME) and prognosis of LUAD. We first used single-cell RNA sequencing data to identify macrophage marker genes in LUAD. Univariate, least absolute shrinkage and selection operator and stepwise multivariate Cox regression analyses were conducted to evaluate macrophage marker genes as prognostic factors and to construct the macrophage marker genes signature (MMGS). A novel 8-gene signature was constructed to predict prognosis based on 465 macrophage marker genes identified by an analysis of single-cell RNA sequencing data of LUAD, and was also verified in 4 independent GEO cohorts. The MMGS significantly classified patients into high-risk and low-risk groups in terms of OS. A prognostic nomogram based on independent risk factors was established to predict the 2-, 3- and 5-year survival, which indicated superior accuracy in predicting prognosis. The high-risk group was correlated to higher tumor mutational burden, number of neoantigens, T-cell receptor richness, and lower TIDE, which suggested that high-risk patients were more likely to benefit from immunotherapy. The prediction of the possibility of immunotherapy efficacy was also discussed. Analysis of an immunotherapy cohort further verified that patients with high-risk scores had better immunotherapy responses than low-risk patients. The MMGS is a promising signature for predicting prognosis and effectiveness of immunotherapy in patients with LUAD, and may be helpful for clinical decision-making.

肺腺癌(LUAD)是全球癌症相关死亡的主要原因。肿瘤相关巨噬细胞在LUAD的肿瘤微环境(tumor microenvironment, TME)和预后中起关键作用。我们首先使用单细胞RNA测序数据来鉴定LUAD中的巨噬细胞标记基因。通过单因素、最小绝对收缩和选择算子以及逐步多因素Cox回归分析来评估巨噬细胞标记基因作为预后因素的作用,并构建巨噬细胞标记基因特征(MMGS)。通过对LUAD单细胞RNA测序数据的分析,鉴定出465个巨噬细胞标记基因,构建了一个新的8基因标记来预测预后,并在4个独立的GEO队列中得到验证。MMGS根据OS将患者分为高危组和低危组。建立基于独立危险因素的预后nomogram预测2、3、5年生存期,预测预后具有较高的准确性。高危组与较高的肿瘤突变负担、新抗原数量、t细胞受体丰富度和较低的TIDE相关,提示高危患者更有可能从免疫治疗中获益。并对免疫治疗疗效的可能性进行了预测。免疫治疗队列分析进一步证实,评分高的患者比低风险患者有更好的免疫治疗反应。MMGS是预测LUAD患者的预后和免疫治疗效果的一个有希望的标志,可能有助于临床决策。
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引用次数: 0
Sintilimab-induced Alopecia Universalis in a Patient With the Anti-tumor Effect of Complete Remission After Hepatectomy. 辛替利单抗诱导的完全性脱发患者肝切除术后完全缓解的抗肿瘤作用。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-07-01 DOI: 10.1097/CJI.0000000000000473
Liang Wen, Jianhui Zhao, Yixiao Yang, Wen Chen, Yingying Bao, Jian Zhang, Tao Wei, Lijuan Zhou, Bin Xi, Yun Zhang, Tingbo Liang

Immune checkpoint blockades have been widely used to treat various malignancies. Programmed cell death protein 1 (PD-1) inhibitor-induced alopecia areata, one of the immune-related adverse events, is rarely reported. We present a case of alopecia universalis during the treatment of Sintilimab, a monoclonal anti-PD-1 antibody, in a patient with hepatocellular carcinoma. A 65-year-old male was diagnosed with hepatocellular carcinoma in liver segment VI (S6) and chose to receive Sintilimab due to predicted insufficient residual liver volume for hepatectomy. He presented extensive hair loss in all the parts of the body 4 weeks after Sintilimab treatment. And without using any dermatologic drug, the alopecia areata gradually developed to be alopecia universalis after Sintilimab continuous treatment for 21 months. The pathological examination of skin revealed remarkable increased lymphocytes infiltration around the hair follicles, which contained predominantly CD8 positive T cells in the dermis. During single immunotherapy, the tumor marker of serum alpha-fetoprotein level soon decreased from 512.1 mg/L to a normal level within 3 months, accompanied with a remarkable tumor regression in liver S6 by magnetic resonance imaging scans. The patient received hepatectomy and pathological examination demonstrated the nodule was full of extensive necrosis. By combining immunotherapy and hepatectomy, the patient finally achieved a remarkable anti-tumor effect of complete remission. Immune checkpoint blockades-induced alopecia areata is a rare immune-related adverse event and accompanied with a good anti-tumor efficacy in our case. Regardless of alopecia treatment, PD-1 inhibitor treatment is recommended to be continued, especially when the immunotherapy is effective.

免疫检查点阻断已广泛用于治疗各种恶性肿瘤。程序性细胞死亡蛋白1 (PD-1)抑制剂诱导的斑秃是免疫相关不良事件之一,报道较少。我们提出了一例普遍脱发的治疗期间辛替单抗,一种单克隆抗pd -1抗体,在一个病人的肝细胞癌。一名65岁男性被诊断为肝VI节段肝癌(S6),由于预测肝切除剩余肝容量不足,选择接受辛替单抗治疗。他在辛替单抗治疗4周后出现全身大面积脱发。在不使用任何皮肤科药物的情况下,经辛替单抗持续治疗21个月后,斑秃逐渐发展为普秃。皮肤病理检查显示毛囊周围淋巴细胞浸润明显增加,真皮以CD8阳性T细胞为主。在单次免疫治疗期间,血清甲胎蛋白肿瘤标志物在3个月内从512.1 mg/L迅速下降到正常水平,并伴有肝S6明显的肿瘤消退。患者行肝切除术,病理检查显示结节充满广泛坏死。通过免疫治疗和肝切除相结合,患者最终取得了显著的抗肿瘤效果,完全缓解。免疫检查点阻断引起的斑秃是一种罕见的免疫相关不良事件,在本病例中具有良好的抗肿瘤疗效。无论脱发治疗如何,建议继续使用PD-1抑制剂治疗,特别是当免疫治疗有效时。
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引用次数: 0
Vitamin D Status Is Associated With Immune Checkpoint Inhibitor Efficacy and Immune-related Adverse Event Severity in Lung Cancer Patients: A Prospective Cohort Study. 肺癌患者维生素D水平与免疫检查点抑制剂疗效和免疫相关不良事件严重程度相关:一项前瞻性队列研究
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-07-01 DOI: 10.1097/CJI.0000000000000469
Wen You, Xinyu Liu, Hao Tang, Bo Lu, Qingyang Zhou, Yue Li, Minjiang Chen, Jing Zhao, Yan Xu, Mengzhao Wang, Jiaming Qian, Bei Tan

Vitamin D (VitD) is potentially immunomodulatory, so here we aimed to explore the relationships between serum VitD levels, immune checkpoint inhibitor (ICI) efficacy, and immune-related adverse events (irAEs). Serum 25-hydroxyvitamin D [25(OH)D] levels were quantified before and after ICI treatment in prospectively enrolled patients with advanced lung cancers. Of 77 enrolled patients, 29 developed 42 irAEs. Baseline 25(OH)D levels of partial response (PRs) patients were significantly higher than non-PR patients (19.39±7.16 vs. 16.28±5.99 ng/mL, P =0.04). The area under the curve of 25(OH)D >15.73 ng/mL to identify PR was 0.63 (95% CI, 0.51-0.76, P =0.047), and baseline 25(OH)D levels >15.73 ng/mL (odds ratio: 2.93, 95% CI, 1.10-7.79, P =0.03) and prior targeted therapy (odds ratio: 0.30, 95% CI, 0.10-0.92, P =0.04) were independent predictors of PR as best efficacy by multivariable logistic regression. With respect to irAEs, baseline 25(OH)D levels were higher in grade 1 irAE patients than in grade 2/3/4 irAE patients (20.07±8.64 vs. 15.22±2.30 ng/mL, P =0.02). However, the area under the curve was only 0.56 (95% CI, 0.42-0.70, P =0.39) for a baseline 25(OH)D of 20.99 ng/mL for predicting irAE occurrence. There was a direct monotonic relationship and U-shaped relationship between baseline 25(OH)D levels and ICI efficacy and irAE occurrence, respectively. Overall survival was significantly different between VitD sufficient, insufficient, and deficient patients (log-rank P =0.01), which remained after adjustment in Cox proportional hazards regression models. Baseline 25(OH)D levels seem to be associated with ICI efficacy and prognosis, it might be helpful to assess the baseline VitD status, and supplementation with VitD might bring some benefit to enhance ICI efficacy and reduce moderate-severe irAEs.

维生素D (VitD)具有潜在的免疫调节作用,因此本研究旨在探讨血清维生素D水平、免疫检查点抑制剂(ICI)疗效和免疫相关不良事件(irAEs)之间的关系。对前瞻性纳入的晚期肺癌患者在ICI治疗前后的血清25-羟基维生素D [25(OH)D]水平进行量化。在77例入组患者中,29例发生了42例irae。部分缓解(pr)患者的基线25(OH)D水平显著高于非pr患者(19.39±7.16∶16.28±5.99 ng/mL, P =0.04)。25(OH)D >15.73 ng/mL诊断PR的曲线下面积为0.63 (95% CI, 0.51 ~ 0.76, P =0.047),基线25(OH)D水平>15.73 ng/mL(优势比:2.93,95% CI, 1.10 ~ 7.79, P =0.03)和既往靶向治疗(优势比:0.30,95% CI, 0.10 ~ 0.92, P =0.04)是多变量logistic回归预测PR最佳疗效的独立预测因子。在irAE方面,1级irAE患者的基线25(OH)D水平高于2/3/4级irAE患者(20.07±8.64 vs 15.22±2.30 ng/mL, P =0.02)。然而,基线25(OH)D为20.99 ng/mL时,预测irAE发生的曲线下面积仅为0.56 (95% CI, 0.42-0.70, P =0.39)。基线25(OH)D水平与ICI疗效和irAE发生分别呈直接单调关系和u型关系。VitD充足、不足和缺乏患者的总生存率存在显著差异(log-rank P =0.01), Cox比例风险回归模型调整后仍存在差异。基线25(OH)D水平似乎与ICI疗效和预后相关,可能有助于评估基线维生素D状态,补充维生素D可能对提高ICI疗效和减少中重度irAEs有一定益处。
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引用次数: 0
TLR Agonist Therapy of Metastatic Breast Cancer in Mice. TLR激动剂治疗小鼠转移性乳腺癌。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-06-01 DOI: 10.1097/CJI.0000000000000467
Dennis M Klinman, Emilie Goguet, Debra Tross

Toll-like receptor (TLR) 7/8 and 9 agonists stimulate an innate immune response that supports the development of tumor-specific immunity. Previous studies showed that either agonist individually could cure mice of small tumors and that when used in combination, they could prevent the progression of larger tumors (>300 mm 3 ). To examine whether these agents combined could control metastatic disease, syngeneic mice were challenged with the highly aggressive 66cl4 triple-negative breast tumor cell line. Treatment was not initiated until pulmonary metastases were established, as verified by bioluminescent imaging of luciferase-tagged tumor cells. Results show that combined therapy with TLR7/8 and TLR9 agonists delivered to both primary and metastatic tumor sites significantly reduced tumor burden and extended survival. The inclusion of cyclophosphamide and anti-PD-L1 resulted in optimal tumor control, characterized by a 5-fold increase in the average duration of survival.

toll样受体(TLR) 7/8和9激动剂刺激先天免疫反应,支持肿瘤特异性免疫的发展。先前的研究表明,这两种激动剂单独使用都可以治愈小鼠的小肿瘤,当它们联合使用时,它们可以阻止较大肿瘤(>300 mm 3)的进展。为了检验这些药物联合使用是否能控制转移性疾病,我们用高侵袭性66cl4三阴性乳腺肿瘤细胞系刺激同基因小鼠。通过荧光素酶标记的肿瘤细胞的生物发光成像证实,直到肺部转移确定后才开始治疗。结果表明,TLR7/8和TLR9激动剂联合治疗原发性和转移性肿瘤,可显著降低肿瘤负担,延长生存期。环磷酰胺和抗pd - l1的加入使肿瘤得到最佳控制,其特点是平均生存时间增加了5倍。
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引用次数: 0
Enhancing the Anti-tumor Potency of a Novel Siglec-15 Antibody by Engineering its Fc-mediated Effector Functions. 一种新型Siglec-15抗体通过改造其fc介导的效应功能来增强其抗肿瘤效力。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-06-01 DOI: 10.1097/CJI.0000000000000465
Huandi Ding, Bing Yao, Lei Ci, Jing Feng, Pingkai Ouyang, Guoguang Chen, Xiwu Hui, Demin Zhou

Siglec-15, an inhibitory immune checkpoint, is an emerging target in cancer immunotherapy. Blocking the function of Siglec-15 is an excellent strategy for cancer treatment and antibody blockade has been used to target Siglec-15. However, whether Fc-mediated effector functions contribute to the therapeutic effect of antibodies remains unclear. Herein, we generated a monoclonal antibody, 1-15D1, which had a high binding affinity with Siglec-15 and strongly activated T-cell immune response in vitro. Subsequently, the Fc-mediated effector functions of 1-15D1 were explored in a Siglec-15 humanized mouse model, and further improvement in antitumor efficacy was observed in the mouse IgG2a isotype group. Thus, we demonstrate that the antitumor effects of 1-15D1 were mediated via multiple factors. In addition to the T-cell immune response, 2 novel mechanisms were explored, including the internalization of the cell surface Siglec-15 and Fc-mediated effector functions. In conclusion, our studies not only provide a potential agent for the improvement of cancer immunotherapy but also suggest that a specific role of Fc-mediated immune regulation may improve the therapeutic potency of Siglec-15 monoclonal antibody.

siglece -15是一种抑制免疫检查点,是癌症免疫治疗的新兴靶点。阻断siglece -15的功能是癌症治疗的一种极好的策略,抗体阻断已被用于靶向siglece -15。然而,fc介导的效应物功能是否有助于抗体的治疗效果尚不清楚。在此,我们制备了一种单克隆抗体1-15D1,该抗体与siglece -15具有高结合亲和力,并在体外强烈激活t细胞免疫反应。随后,我们在siglece -15人源化小鼠模型中探索了fc介导的1-15D1效应物功能,并在小鼠IgG2a同型组中观察到其抗肿瘤功效的进一步提高。因此,我们证明了1-15D1的抗肿瘤作用是通过多种因素介导的。除了t细胞免疫应答外,研究人员还探索了2种新的机制,包括细胞表面siglece -15的内化和fc介导的效应功能。综上所述,我们的研究不仅为改善癌症免疫治疗提供了一种潜在的药物,而且表明fc介导的免疫调节的特定作用可能提高siglece -15单克隆抗体的治疗效力。
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引用次数: 0
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Journal of Immunotherapy
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