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Mucin-1-Targeted Chimeric Antigen Receptor T Cells Are Effective and Safe in Controlling Solid Tumors in Immunocompetent Host. 以 Mucin-1 为靶点的嵌合抗原受体 T 细胞能有效、安全地控制免疫功能正常宿主的实体瘤。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-04-01 Epub Date: 2024-01-25 DOI: 10.1097/CJI.0000000000000505
Ru Zhou, Shu-Ta Wu, Mahboubeh Yazdanifar, Chandra Williams, Alexa Sanders, Cory Brouwer, John Maher, Pinku Mukherjee

The chimeric antigen receptor (CAR) T-cell therapy in solid epithelial tumors has been explored, however, with limited success. As much of the preclinical work has relied on xenograft models in immunocompromised animals, the immune-related efficacies and toxicities may have been missed. In this study, we engineered syngeneic murine CAR T cells targeting the tumor form of human mucin-1 (tMUC1) and tested the MUC1 CAR T cells' efficacy and toxicity in the immunocompetent human MUC1-expressing mouse models. The MUC1 CAR T cells significantly eliminated murine pancreatic and breast cancer cell lines in vitro. In vivo, MUC1 CAR T cells significantly slowed the mammary gland tumor progression in the spontaneous PyVMT×MUC1.Tg (MMT) mice, prevented lung metastasis, and prolonged survival. Most importantly, there was minimal short or long-term toxicity with acceptable levels of transient liver toxicity but no kidney toxicity. In addition, the mice did not show any signs of weight loss or other behavioral changes with the treatment. We also report that a single dose of MUC1 CAR T-cell treatment modestly reduced the pancreatic tumor burden in a syngeneic orthotopic model of pancreatic ductal adenocarcinoma given at late stage of an established tumor. Taken together, these findings suggested the further development of tMUC1-targeted CAR T cells as an effective and relatively safe treatment modality for various tMUC1-expressing solid tumors.

对实体上皮肿瘤的嵌合抗原受体(CAR)T 细胞疗法进行了探索,但成效有限。由于大部分临床前研究都依赖于免疫受损动物的异种移植模型,因此可能会忽略与免疫相关的疗效和毒性。在这项研究中,我们设计了以肿瘤形式的人类粘蛋白-1(tMUC1)为靶点的同种异体小鼠 CAR T 细胞,并在免疫功能正常的人类 MUC1 表达小鼠模型中测试了 MUC1 CAR T 细胞的疗效和毒性。在体外,MUC1 CAR T 细胞能明显消除小鼠胰腺癌和乳腺癌细胞系。在体内,MUC1 CAR T细胞明显减缓了自发性PyVMT×MUC1.Tg(MMT)小鼠乳腺肿瘤的进展,防止了肺转移,延长了生存期。最重要的是,小鼠的短期或长期毒性极小,一过性肝脏毒性水平可接受,但肾脏无毒性。此外,小鼠在治疗过程中没有出现任何体重减轻或其他行为变化的迹象。我们还报告说,在胰腺导管腺癌成熟晚期,单剂量 MUC1 CAR T 细胞治疗可适度减轻胰腺肿瘤负荷。综上所述,这些研究结果表明,tMUC1靶向CAR T细胞是治疗各种表达tMUC1的实体瘤的一种有效且相对安全的方法。
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引用次数: 0
Pathologic Complete Response After Gastric Artery Chemoembolization Combined With Tislelizumab for Neoadjuvant Therapy of Locally Advanced Gastric Cancer: A Case Report. 胃动脉化疗栓塞联合替利单抗新辅助治疗局部晚期胃癌病理完全缓解1例
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-04-01 Epub Date: 2023-11-23 DOI: 10.1097/CJI.0000000000000488
Yufu Lin, Yabo Chen, Shenggan Lin, Jingmei Zheng, Xiuping Zhang, Lu Gan

Gastric cancer is the most common type of gastrointestinal cancer in China which about 80% of patients are locally advanced or advanced when diagnosed. Surgery along brings high recurrence rate for locally advanced gastric cancer (LAGC), and neoadjuvant therapies are needed. The use of programmed cell death-1 (PD-1)/programmed death-ligand 1 inhibitor nowadays improved the disease-free survival for LAGC, however, only <35% of patients achieved pathologic complete response (pCR) after neoadjuvant therapy nowadays. Therefore, new regimens are needed to be investigated. Gastric artery chemoembolization is applied to metastasis gastric cancer and researches showed interventional therapy can enhance the antitumor effect of PD-1 inhibitor. Here, for the first time, we combined gastric artery chemoembolization with tislelizumab (a PD-1 inhibitor) for neoadjuvant therapy of a patient with LAGC. The patient achieved pCR after a D2 resection and tumor regression grade score was 1. After surgery, the patient received tislelizumab 200 mg per 3 weeks, and showed no sign of recurrence after 6 months of follow-up. The study indicated the use of tislelizumab and gastric artery chemoembolization for neoadjuvant therapy may bring a better pCR rate and prognosis of LAGC.

胃癌是中国最常见的胃肠道肿瘤类型,约80%的患者在确诊时为局部晚期或晚期。局部进展期胃癌(LAGC)术后复发率高,需要新辅助治疗。目前使用程序性细胞死亡-1 (PD-1)/程序性死亡配体-1抑制剂可改善LAGC的无病生存
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引用次数: 0
A New Method for Constructing Macrophage-Associated Predictors of Treatment Efficacy Based on Single-Cell Sequencing Analysis. 基于单细胞测序分析构建巨噬细胞相关治疗效果预测因子的新方法
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-02-01 Epub Date: 2023-11-20 DOI: 10.1097/CJI.0000000000000497
Jianxiu Lin, Yang Ran, Tengfei Wu, Zishan Wang, Jinjin Zhao, Yun Tian

Tumor-associated macrophages (TAMs) are highly infiltrated in the tumor microenvironment (TME) of colorectal cancer (CRC) and play a vital role in CRC's development as well as prognosis. The required data were obtained from the Gene Expression Omnibus database and The Cancer Genome Atlas. Univariate Cox regression and least absolute shrinkage operator analyses were executed for model construction. TME assessment and immune prediction were performed using the ESTIMATE software package and the single sample genome enrichment analysis algorithm. The results show patients with low a TAMs risk score (TRS) had a better prognosis in both The Cancer Genome Atlas and Gene Expression Omnibus cohorts. Patients with low TRS were more sensitive to 3 chemotherapeutic agents: oxaliplatin, paclitaxel, and cisplatin ( P <0.05). TME assessment showed that the low TRS group had less infiltration of M2 macrophages and regulatory T cells, but CD4 + T cells, NK cells, and dendritic cells occupy a greater proportion of TME. Low TRS group patients have a low StromalScore and ImmuneScore but have high TumorPurity. The immune checkpoint TIM-3 gene HAVCR2 expression was significantly higher in the high TRS group. Finally, we created a nomogram including TRS for forecasting survival, and TRS was significantly associated with the clinical stage of the patients. In conclusion, the TRS serves as a reliable prognostic indicator of CRC; it predicts patient outcomes to immunotherapy and chemotherapy and provides genomic evidence for the subsequent development of modulated TAMs for treating CRC.

肿瘤相关巨噬细胞(tumor -associated macrophages, tam)高度浸润于结直肠癌(CRC)的肿瘤微环境(tumor microenvironment, TME)中,在结直肠癌的发生发展和预后中起着至关重要的作用。所需数据来自基因表达综合数据库和癌症基因组图谱。单变量Cox回归和最小绝对收缩算子分析用于模型构建。采用ESTIMATE软件包和单样本基因组富集分析算法进行TME评估和免疫预测。结果显示,在The Cancer Genome Atlas和Gene Expression Omnibus队列中,TAMs风险评分(TRS)较低的患者预后较好。低TRS患者对奥沙利铂、紫杉醇和顺铂3种化疗药物更敏感(P
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引用次数: 0
Core Needle Biopsies as an Alternative Source for Ex Vivo Expanded TIL for Adoptive Cell Therapy in Triple-Negative Breast Cancer. 核心针活检作为三阴性乳腺癌过继细胞治疗的体外扩展TIL的替代来源。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-02-01 Epub Date: 2023-11-22 DOI: 10.1097/CJI.0000000000000495
Magdalena M Coman, Lajos Pusztai, Regina Hooley, Liva Andreveja, Leah Kim, Nikhil Joshi, Alexey Bersenev, Diane Krause, Tristen S Park

Adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes (TILs) have produced long-term response in metastatic cancers. TILs have traditionally been expanded from surgically resected specimens. Ultrasound-guided core needle biopsy (CNB) is an alternative method that avoids the morbidity of surgery and have added benefits which may include patients not amenable to surgery as well as the potential to produce TILs from multiple lesions in the same patient. We assessed the ability to produce and expand TILs from primary triple-negative breast cancer tumors from CNB (n=7) and demonstrate comparable expansion, phenotype and cytokine secretion after phorbol myristate acetate-ionomycin stimulation to TILs expanded from surgery (n=6). T cell Receptor clonality and diversity were also comparable between the two cohorts throughout the TIL culture. CNB is a safe and feasible method to obtain tumor tissue for TIL generation in patients with triple-negative breast cancer.

体外扩增肿瘤浸润淋巴细胞(TILs)的过继转移在转移性癌症中产生了长期的反应。传统上,til是从手术切除的标本中扩展出来的。超声引导下的核心穿刺活检(CNB)是一种替代方法,它避免了手术的发病率,并有额外的好处,可能包括不适合手术的患者,以及同一患者的多个病变产生TILs的潜力。我们评估了来自CNB的原发性三阴性乳腺癌肿瘤产生和扩大TILs的能力(n=7),并证明了在肉豆酸酯-离子霉素刺激后,TILs的扩大、表型和细胞因子分泌与手术后扩大的TILs相当(n=6)。在整个TIL培养过程中,两个队列之间的T细胞受体克隆性和多样性也具有可比性。CNB是三阴性乳腺癌患者获取肿瘤组织用于TIL生成的一种安全可行的方法。
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引用次数: 0
LOXL4 Shuttled by Tumor Cells-derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis. 肿瘤细胞来源的细胞外囊泡通过激活STAT1/PD-L1轴促进肝细胞癌的免疫逃逸
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-02-01 Epub Date: 2023-12-04 DOI: 10.1097/CJI.0000000000000496
Le Zhao, Ruifeng Pei, Yiren Ding, Zhan Su, Deqiang Li, Shuo Zhu, Lu Xu, Hongying Zhao, Wuyuan Zhou

Emerging evidence has validated that extracellular vesicles (EVs) regulate hepatocellular carcinoma (HCC) progression, while its role in HCC immune escape remains to be elucidated. This study investigates the role of EVs-encapsulated lysyl oxidase like-4 (LOXL4) derived from tumor cells in HCC immune escape. HCC-related microarray data sets GSE36376 and GSE87630 were obtained for differential analysis, followed by identifying the essential genes related to the prognosis of HCC patients. Bone marrow-derived macrophages were treated with EVs derived from mouse Hepa 1-6 cells and cocultured with CD8 + T cells to observe the CD8 + T-cell activity. At last, a mouse HCC orthotopic xenograft model was constructed to verify the effects of HCC cell-derived EVs on the immune escape of HCC cells and tumorigenicity in vivo by delivering LOXL4. It was found that ACAT1, C4BPA, EHHADH, and LOXL4 may be the essential genes related to the prognosis of HCC patients. On the basis of the TIMER database, there was a close correlation between LOXL4 and macrophage infiltration in HCC. Besides, STAT1 was closely related to LOXL4. In vitro experiments demonstrated that LOXL4 could induce programmed death-ligand 1 expression in macrophages and immunosuppression by activating STAT1. In vivo experiments also verified that HCC cell-derived EVs promoted the immune escape of HCC cells and tumorigenicity by delivering LOXL4. LOXL4 was delivered into macrophages via EVs to induce programmed death-ligand 1 by activating STAT1 and inhibiting the killing ability of CD8 + T cells to HCC cells, thus promoting immune escape in HCC.

新出现的证据证实,细胞外囊泡(EVs)调节肝细胞癌(HCC)的进展,但其在HCC免疫逃逸中的作用仍有待阐明。本研究探讨来自肿瘤细胞的ev包封赖氨酸氧化酶样4 (LOXL4)在HCC免疫逃逸中的作用。获取HCC相关微阵列数据集GSE36376和GSE87630进行差异分析,确定与HCC患者预后相关的必要基因。用小鼠Hepa 1-6细胞衍生的ev处理骨髓源性巨噬细胞,并与CD8+ T细胞共培养,观察CD8+ T细胞活性。最后,构建小鼠肝癌原位异种移植模型,验证肝癌细胞源性ev通过传递LOXL4对肝癌细胞免疫逃逸和体内致瘤性的影响。我们发现ACAT1、C4BPA、EHHADH、LOXL4可能是与HCC患者预后相关的重要基因。根据TIMER数据库,肝癌中LOXL4与巨噬细胞浸润密切相关。此外,STAT1与LOXL4密切相关。体外实验表明,LOXL4可通过激活STAT1诱导巨噬细胞程序性死亡配体1的表达和免疫抑制。体内实验也证实了肝细胞源性ev通过传递LOXL4促进肝细胞的免疫逃逸和致瘤性。LOXL4通过EVs进入巨噬细胞,通过激活STAT1,抑制CD8+ T细胞对HCC细胞的杀伤能力,诱导程序性死亡配体1,从而促进HCC的免疫逃逸。
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引用次数: 0
The Proportion of Myeloid-derived Suppressor Cells in the Graft as a Potential Predictor of Acute Graft-versus-host Disease in Haploid Allogeneic Hematopoietic Stem Cell Transplantation. 移植物中髓源性抑制细胞的比例是单倍体异基因造血干细胞移植中急性移植物抗宿主疾病的潜在预测指标。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-02-01 Epub Date: 2023-12-12 DOI: 10.1097/CJI.0000000000000499
Junjie Cao, Renzhi Pei, Ying Lu, Dong Chen, Xiaohong Du, Xuhui Liu, Shuangyue Li

Myeloid-derived suppressor cells (MDSC) are powerful immunomodulatory cells that play an important role in infectious and inflammatory disorders, but the correlation between graft MDSC amount and early transplant outcomes remains unknown in allogeneic hematopoietic stem cell transplantation. We collected data from 91 patients with acute leukemia undergoing haploidentical allogeneic hematopoietic stem cell transplantation. The grafts were analyzed in terms of CD34+ cells, CD3+ T cells and subpopulation, and MDSC (HLA-DR -/low CD33 + CD16 - ) by flow cytometry. The cutoff value of the MDSC proportion in the graft on the receiver operating curve was 8.89%, with a sensitivity of 0.833 and specificity of 0.852. Day +100 cumulative incidences of II-IV and III-IV acute graft-versus-host disease (aGVHD) in the low MDSC group were 73.5% and 38.8%, respectively, and that in the high MDSC group were 5.3% and 0%, with a significant difference in incidences of II-IV and III-IV aGVHD ( P <0.001). The overall survival, relapse-free survival, and GVHD-relapse-free survival (GRFS) at 1 year were 66.3% versus 80.5% ( P =0.043), 71.6% versus 71.7% ( P =0.248), and 22.1% versus 62.8% ( P <0.001), respectively. No significant difference in the cumulative incidence of relapse between the 2 groups was observed. Multivariate analysis revealed that higher MDSC proportions were associated with a lower risk of II-IV aGVHD. Graft MDSC proportion exceeding 8.89% was significantly associated with higher overall survival and GRFS. The prophylaxis of antithymocyte globulin+post-transplant cyclophosphamide and higher MDSC proportion in the graft were favorable factors for improving GRFS. In conclusion, graft MDSC proportion may be a significant predictor of aGVHD.

髓源性抑制细胞(MDSC)是一种强大的免疫调节细胞,在感染性和炎症性疾病中发挥着重要作用,但在异体造血干细胞移植中,移植物MDSC数量与早期移植结果之间的相关性仍然未知。我们收集了91名接受单倍体异基因造血干细胞移植的急性白血病患者的数据。通过流式细胞术分析了移植物中的CD34+细胞、CD3+ T细胞和亚群以及MDSC(HLA-DR-/低CD33+CD16-)。在接收者操作曲线上,移植物中 MDSC 比例的临界值为 8.89%,灵敏度为 0.833,特异度为 0.852。第 +100 天,低 MDSC 组 II-IV 和 III-IV 急性移植物抗宿主病(aGVHD)的累积发生率分别为 73.5% 和 38.8%,而高 MDSC 组分别为 5.3% 和 0%,II-IV 和 III-IV aGVHD 的发生率差异显著(P<0.05)。
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引用次数: 0
Effectiveness and Safety of Immune Checkpoint Inhibitors in Cancer Patients With Autoimmune Disease: A Retrospective Cohort Study. 癌症自身免疫性疾病患者免疫检查点抑制剂的有效性和安全性:回顾性队列研究。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-11-06 DOI: 10.1097/CJI.0000000000000492
Arjun A Raghavan, Sid Goutam, Grace Musto, Marc Geirnaert, Carrie Ye, Liam J O'Neil, Jeffrey Graham

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, patients with pre-existing autoimmune diseases (PADs) have largely been excluded from clinical trials evaluating this drug class. This study evaluates the effectiveness and safety of ICI therapy in individuals with PAD in a real-world setting. A retrospective study of patients exposed to ICI therapy between 2012 and 2019 was conducted. Patients with PAD were identified and matched to an ICI-exposed group without PAD based on age, sex, and cancer type. Primary outcomes included toxicity, time to treatment failure, overall survival, and objective response rate. The association between PAD status and outcomes was determined using Cox and logistic regression modeling. A total of 813 patients exposed to ICI therapy were identified, of which 8.2% (N=67) had a PAD. When compared with a matched cohort without PAD (N=132), there was no significant difference in the rates of new immune-related adverse events (irAEs, 42.4% in the non-PAD group vs. 47.8% in the PAD group, P=0.474). After controlling for the type of ICI, there was no significant association between PAD status and irAE (odds ratio 1.67, 95% CI: 0.9-3.21 P=0.1). There was no significant association between overall survival and PAD status (hazard ratio 1.12, 95% CI: 0.76-1.66. P=0.56) or between time to treatment failure and PAD status (hazard ratio 0.82, 95% CI: 0.6-1.12, P=0.22). There was an association between PAD status and objective response rate (odds ratio 3.28, 95% CI: 1.28-8.38, P=0.013). In summary, PAD status was not associated with enhanced toxicity when compared with patients without PAD, with similar oncologic effectiveness between these 2 groups.

尽管免疫检查点抑制剂(ICIs)已经彻底改变了癌症治疗,但已有自身免疫性疾病(PADs)的患者在很大程度上被排除在评估该药物类别的临床试验之外。本研究评估了ICI治疗PAD患者的有效性和安全性。对2012年至2019年间接受ICI治疗的患者进行了回顾性研究。根据年龄、性别和癌症类型,确定PAD患者,并将其与不患有PAD的ICI暴露组进行匹配。主要结果包括毒性、治疗失败时间、总生存率和客观反应率。PAD状态和结果之间的相关性使用Cox和逻辑回归模型确定。共确定813名接受ICI治疗的患者,其中8.2%(N=67)患有PAD。与没有PAD的匹配队列(N=132)相比,新的免疫相关不良事件发生率没有显著差异(irAE,非PAD组42.4%,PAD组47.8%,P=0.474),PAD状态与irAE之间没有显著相关性(比值比1.67,95%CI:0.9-3.21 P=0.1)。总生存率与PAD状态之间没有显著关联(危险比1.12,95%CI:0.76-1.66)。P=0.56)或治疗失败时间与PAD状态之间(危险比0.82,95%CI:0.6-12,P=0.22)。PAD状态与客观缓解率之间存在相关性(比值比3.28,95%CI:1.28-8.38,P=0.013)。总之,与无PAD的患者相比,PAD状态不与毒性增强相关,这两组之间的肿瘤学有效性相似。
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引用次数: 0
Effect of Concomitant Use of Proton Pump Inhibitors on Immunotherapy Clinical Response in Advanced Cancer Patients: Real-Life Setting. 同时使用质子泵抑制剂对晚期癌症患者免疫治疗临床反应的影响:现实生活环境。
IF 3.9 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-11-06 DOI: 10.1097/CJI.0000000000000494
Lorenzo Cantarelli, Fernando Gutiérrez Nicolás, Sara García Gil, Jose A Morales Barrios, Juana Oramas Rodriguez, Gloria J Nazco Casariego

The alteration of the gut microbiota mediated by proton pump inhibitor (PPI) drugs could be involved in the clinical response associated with immunotherapy [immunocheckpoint inhibitors (ICIs)] in cancer patients. Due to the current controversy in the scientific evidence, it has been proposed to evaluate the correlation between the concomitant use of PPIs and the effectiveness of immunotherapy in a real clinical practice setting. Single-center retrospective cohort study that included patients treated with anti-PD-1 or anti-CTLA4, including nivolumab, pembrolizumab, atezolizumab, or the combination ipilimumab-nivolumab in metastatic neoplastic disease. The clinical effectiveness of ICI, measured in progression-free survival (PFS) and overall survival (OS), was compared between the PPI-use versus PPI-no-use group. PPI-use group was associated with lower PFS [hazard ratio (HR):1.89 (1.38-2.59), P<0.001] and OS [HR: 2.02 (1.45-2.82), P<0.001] versus PPI-no-use group. However, this difference was not observed for pembrolizumab PFS [HR: 1.38 (0.93-2.39), P=0.160] and OS [HR: 1.41 (0.81-2.44), P=0.187]. The study showed significantly lower PFS and OS in the chronic PPI-use group (P<0.001), recent PPI-use group (P<0.001) and concomitant PPI-use group (P=0.001, 0.007) versus PPI-no-use group. However, late PPI use >30 days after the onset of ICI has no significant effect on the efficacy of treatment [HR: 0.92 (0.49-1.70), P=0.791; HR: 1.10 (0.59-2.05), P=0.756]. The concomitant use of PPIs in immunotherapy is associated with worse clinical outcomes compared with the group without PPI use. In addition, the study shows how the late use of PPIs does not have a significant effect on clinical benefit.

质子泵抑制剂(PPI)药物介导的肠道微生物群的改变可能与癌症患者免疫疗法[免疫检查点抑制剂(ICIs)]相关的临床反应有关。由于目前科学证据存在争议,有人提出在实际临床实践中评估PPIs的同时使用与免疫疗法有效性之间的相关性。单中心回顾性队列研究,包括在转移性肿瘤疾病中接受抗PD-1或抗CTLA4治疗的患者,包括nivolumab、pembrolizumab、atezolizumab或ipilimumab-niovolumab组合。在PPI使用组和PPI不使用组之间比较ICI的临床有效性,以无进展生存期(PFS)和总生存期(OS)衡量。PPI使用组PFS较低[危险比(HR):1.89(1.38-2.59),ICI发作后P30天对治疗效果没有显著影响[HR:0.92(0.49-1.70),P=0.791;HR:1.10(0.59-2.05),P=0.756]。与未使用PPI的组相比,在免疫治疗中同时使用PPI与更差的临床结果相关。此外,该研究表明,PPI的后期使用对临床益处没有显著影响。
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引用次数: 0
Predicting PD-L1 Status in Solid Tumors Using Transcriptomic Data and Artificial Intelligence Algorithms 利用转录组学数据和人工智能算法预测实体肿瘤中PD-L1的状态
4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-11-02 DOI: 10.1097/cji.0000000000000489
Ahmad Charifa, Alfonso Lam, Hong Zhang, Andrew Ip, Andrew Pecora, Stanley Waintraub, Deena Graham, Donna McNamara, Martin Gutierrez, Andrew Jennis, Ipsa Sharma, Jeffrey Estella, Wanlong Ma, Andre Goy, Maher Albitar
Programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) is routinely used to predict the clinical response to immune checkpoint inhibitors (ICIs); however, multiple assays and antibodies have been used. This study aimed to evaluate the potential of targeted transcriptome and artificial intelligence (AI) to determine PD-L1 RNA expression levels and predict the ICI response compared with traditional IHC. RNA from 396 solid tumors samples was sequenced using next-generation sequencing (NGS) with a targeted 1408-gene panel. RNA expression and PD-L1 IHC were assessed across a broad range of PD-L1 expression levels. AI was used to predict the PD-L1 status. PD-L1 RNA levels assessed by NGS demonstrated robust linearity across high and low expression ranges, and those assessed using NGS and IHC (tumor proportion score and tumor-infiltrating immune cells) had a similar pattern. RNA sequencing provided in-depth information on the tumor microenvironment and immune response, including CD19, CD22, CD8A, CTLA4 , and PD-L2 expression status. Subanalyses showed a sustained correlation of mRNA expression with IHC (tumor proportion score and immune cells) across different solid tumor types. Machine learning showed high accuracy in predicting PD-L1 status, with the area under the curve varying between 0.83 and 0.91. Targeted transcriptome sequencing combined with AI is highly useful for predicting PD-L1 status. Measuring PD-L1 mRNA expression by NGS is comparable to measuring PD-L1 expression by IHC for predicting ICI response. RNA expression has the added advantages of being amenable to standardization and avoiding interpretation bias, along with an in-depth evaluation of the tumor microenvironment.
程序性死亡配体-1 (PD-L1)免疫组织化学(IHC)通常用于预测对免疫检查点抑制剂(ICIs)的临床反应;然而,已经使用了多种检测方法和抗体。本研究旨在评估靶向转录组和人工智能(AI)与传统IHC相比在确定PD-L1 RNA表达水平和预测ICI反应方面的潜力。利用新一代测序技术(NGS)对396例实体瘤样本的RNA进行了靶向1408基因测序。在广泛的PD-L1表达水平范围内评估RNA表达和PD-L1 IHC。AI预测PD-L1状态。NGS评估的PD-L1 RNA水平在高表达范围和低表达范围内显示出强大的线性,使用NGS和IHC(肿瘤比例评分和肿瘤浸润免疫细胞)评估的PD-L1 RNA水平具有相似的模式。RNA测序提供了肿瘤微环境和免疫应答的深入信息,包括CD19、CD22、CD8A、CTLA4和PD-L2的表达状态。亚分析显示,mRNA表达与不同实体瘤类型的IHC(肿瘤比例评分和免疫细胞)持续相关。机器学习对PD-L1状态的预测准确率较高,曲线下面积在0.83 ~ 0.91之间变化。靶向转录组测序结合人工智能在预测PD-L1状态方面非常有用。通过NGS测量PD-L1 mRNA表达与通过IHC测量PD-L1表达预测ICI反应相当。RNA表达具有标准化和避免解释偏差的额外优势,以及对肿瘤微环境的深入评估。
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引用次数: 0
Antigen-loaded Monocyte Administration and Flt3 Ligand Augment the Antitumor Efficacy of Immune Checkpoint Blockade in a Murine Melanoma Model. 抗原负载的单核细胞给药和Flt3配体增强小鼠黑色素瘤模型中免疫检查点阻断的抗肿瘤效力。
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2023-11-01 Epub Date: 2023-09-20 DOI: 10.1097/CJI.0000000000000487
Vincent M D'Anniballe, Min-Nung Huang, Benjamin D Lueck, Lowell T Nicholson, Ian McFatridge, Michael D Gunn

Undifferentiated monocytes can be loaded with tumor antigens (Ag) and administered intravenously to induce antitumor cytotoxic T lymphocyte (CTL) responses. This vaccination strategy exploits an endogenous Ag cross-presentation pathway, where Ag-loaded monocytes (monocyte vaccines) transfer their Ag to resident splenic dendritic cells (DC), which then stimulate robust CD8 + CTL responses. In this study, we investigated whether monocyte vaccination in combination with CDX-301, a DC-expanding cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), could improve the antitumor efficacy of anti-programmed cell death (anti-PD-1) immune checkpoint blockade. We found that Flt3L expanded splenic DC over 40-fold in vivo and doubled the number of circulating Ag-specific T cells when administered before monocyte vaccination in C57BL/6 mice. In addition, OVA-monocyte vaccination combined with either anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), or anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) suppressed subcutaneous B16/F10-OVA tumor growth to a greater extent than checkpoint blockade alone. When administered together, OVA-monocyte vaccination improved the antitumor efficacy of Flt3L and anti-PD-1 in terms of circulating Ag-specific CD8 + T cell frequency and inhibition of subcutaneous B16/F10-OVA tumor growth. To our knowledge, this is the first demonstration that a cancer vaccine strategy and Flt3L can improve the antitumor efficacy of anti-PD-1. The findings presented here warrant further study of how monocyte vaccines can improve Flt3L and immune checkpoint blockade as they enter clinical trials.

未分化的单核细胞可以负载肿瘤抗原(Ag)并静脉内给药以诱导抗肿瘤细胞毒性T淋巴细胞(CTL)反应。这种疫苗接种策略利用内源性Ag交叉呈递途径,其中负载Ag的单核细胞(单核细胞疫苗)将其Ag转移到驻留的脾树突状细胞(DC),然后刺激强大的CD8+CTL反应。在本研究中,我们研究了单核细胞疫苗接种与CDX-301(一种DC扩增细胞因子Fms样酪氨酸激酶3配体(Flt3L))联合是否可以提高抗程序性细胞死亡(抗PD-1)免疫检查点阻断的抗肿瘤疗效。我们发现,Flt3L在C57BL/6小鼠单核细胞接种前给药时,使脾脏DC在体内扩增了40倍以上,并使循环Ag特异性T细胞的数量增加了一倍。此外,与单独的检查点阻断相比,OVA单核细胞疫苗接种与抗PD-1、抗程序性细胞死亡配体1(抗PD-L1)或抗细胞毒性T淋巴细胞抗原-4(抗CTLA-4)联合在更大程度上抑制皮下B16/F10-OVA肿瘤生长。当同时给药时,OVA单核细胞疫苗在循环Ag特异性CD8+T细胞频率和抑制皮下B16/F10-OVA肿瘤生长方面提高了Flt3L和抗PD-1的抗肿瘤功效。据我们所知,这首次证明癌症疫苗策略和Flt3L可以提高抗PD-1的抗肿瘤效力。本文的发现值得进一步研究单核细胞疫苗在进入临床试验时如何改善Flt3L和免疫检查点阻断。
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Journal of Immunotherapy
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