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Whole stromal fibroblast signature is linked to specific chemokine and immune infiltration patterns and to improved survival in NSCLC. 整个基质成纤维细胞特征与特定趋化因子和免疫浸润模式以及 NSCLC 存活率的提高有关。
IF 7.2 2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-11-28 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2274130
Stefan Koeck, Arno Amann, Johan Kern, Marit Zwierzina, Edith Lorenz, Sieghart Sopper, Heinz Zwierzina, Finn Mildner, Martina Sykora, Susanne Sprung, Hubert Hackl, Florian Augustin, Hubert T Maier, Andreas Pircher, Georg Pall, Dominik Wolf, Gabriele Gamerith

Cancer associated fibroblasts (CAF) are known to orchestrate multiple components of the tumor microenvironment, whereas the influence of the whole stromal-fibroblast compartment is less understood. Here, an extended stromal fibroblast signature was investigated to define its impact on immune cell infiltration. The lung cancer adenocarcinoma (LUAD) data set of the cancer genome atlas (TCGA) was used to test whole stroma signatures and cancer-associated fibroblast signatures for their impact on prognosis. 3D cell cultures of the NSCLC cancer cell line A549 together with the fibroblast cell line SV80 were used in combination with infiltrating peripheral blood mononuclear cells (PBMC) for in-vitro investigations. Immune cell infiltration was assessed via flow cytometry, chemokines were analyzed by immunoassays and RNA microarrays. Results were confirmed in specimens from NSCLC patients by flow cytometry or immunohistochemistry as well as in the TCGA data set. The TCGA analyses correlated the whole stromal-fibroblast signature with an improved outcome, whereas no effect was found for the CAF signatures. In 3D microtumors, the presence of fibroblasts induced infiltration of B cells and CD69+CD4+ T cells, which was linked to an increased expression of CCL13 and CXCL16. The stroma/lymphocyte interaction was confirmed in NSCLC patients, as stroma-rich tumors displayed an elevated B cell count and survival in the local cohort and the TCGA data set. A whole stromal fibroblast signature was associated with an improved clinical outcome in lung adenocarcinoma and in vitro and in vivo experiments suggest that this signature increases B and T cell recruitment via induction of chemokines.

众所周知,癌症相关成纤维细胞(CAF)可协调肿瘤微环境的多种成分,而对整个基质成纤维细胞区系的影响却不甚了解。本文研究了基质成纤维细胞的扩展特征,以确定其对免疫细胞浸润的影响。癌症基因组图谱(TCGA)中的肺癌腺癌(LUAD)数据集用于测试整个基质特征和癌症相关成纤维细胞特征对预后的影响。在体外研究中,使用了NSCLC癌细胞株A549和成纤维细胞株SV80的三维细胞培养物以及浸润的外周血单核细胞(PBMC)。免疫细胞浸润通过流式细胞术进行评估,趋化因子通过免疫测定和 RNA 微阵列进行分析。通过流式细胞术或免疫组化法以及 TCGA 数据集对 NSCLC 患者标本的结果进行了确认。TCGA分析结果显示,整个基质-成纤维细胞特征与预后改善相关,而CAF特征则没有影响。在三维微瘤中,成纤维细胞的存在诱导了B细胞和CD69+CD4+ T细胞的浸润,这与CCL13和CXCL16的表达增加有关。基质/淋巴细胞的相互作用在NSCLC患者中得到了证实,因为在本地队列和TCGA数据集中,富含基质的肿瘤显示出B细胞数量和存活率的升高。整个基质成纤维细胞特征与肺腺癌临床预后的改善有关,体外和体内实验表明,该特征通过诱导趋化因子增加了B细胞和T细胞的募集。
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引用次数: 0
Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer 在接受派姆单抗治疗早期三阴性乳腺癌的患者中,免疫相关不良事件的出现与病理完全缓解相关
2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-11-13 DOI: 10.1080/2162402x.2023.2275846
Maximilian Marhold, Simon Udovica, Anna Halstead, Mona Hirdler, Muna Ferner, Kerstin Wimmer, Zsuzsanna Bago-Horvath, Ruth Exner, Florian Fitzal, Kathrin Strasser-Weippl, Tim Robinson, Rupert Bartsch
Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse. In this multicenterretrospective analysis, we characterized real-world incidence of irAEs and treatment outcomes such as pathological complete response (pCR) from the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for eTNBC.
基于KEYNOTE-522试验的结果和监管机构的批准,pembrolizumab在化疗中添加现在是早期三阴性乳腺癌(eTNBC)(临床II-III期)治疗的标准护理。Pembrolizumab是一种程序性细胞死亡蛋白1单克隆抗体,已知会在相当一部分患者中引起免疫相关不良事件(irAEs)。在eTNBC治疗的背景下,关于irae的发生率、类型和治疗策略的实际数据很少。在这项多中心回顾性分析中,我们描述了真实世界中irae的发生率和治疗结果,如派姆单抗和化疗联合作为eTNBC新辅助治疗的病理完全缓解(pCR)。
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引用次数: 0
Immunogenic chemotherapy sensitizes RAS-mutated colorectal cancers to immune checkpoint inhibitors 免疫原性化疗使ras突变的结直肠癌对免疫检查点抑制剂敏感
2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-11-09 DOI: 10.1080/2162402x.2023.2272352
Lucillia Bezu, Oliver Kepp, Guido Kroemer
Recent clinical trials have compared the use of different chemotherapeutic regimens as “immune induction therapies” to sensitize cancers to immune checkpoint inhibitors (ICI). Cytotoxic drugs reputed to be inducers of immunogenic cell death (ICD) appeared to be particularly efficient for this purpose. A trial published in Nature Medicine by Thibaudin et al. reveals the capacity of oxaliplatin-based chemotherapy to sensitize RAS-mutant unresectable metastatic colorectal cancer to ICIs blocking CTLA-4 and PD-L1.
最近的临床试验比较了不同化疗方案作为“免疫诱导疗法”的使用,以使癌症对免疫检查点抑制剂(ICI)敏感。细胞毒性药物被认为是免疫原性细胞死亡(ICD)的诱导剂,在这方面似乎特别有效。Thibaudin等人在《自然医学》上发表的一项试验揭示了奥沙利铂为基础的化疗能够使ras突变的不可切除的转移性结直肠癌对阻断CTLA-4和PD-L1的ICIs敏感。
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引用次数: 0
Next-generation CTLA-4 targeting molecules and combination therapy: promising strategies for improving cancer immunotherapy. 下一代CTLA-4靶向分子和联合治疗:改善癌症免疫疗法的有前景的策略。
IF 7.2 2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-11-05 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2275333
Nils-Petter Rudqvist, Manushak Avagyan, Dhan Chand

Radiation therapy and anti-CTLA-4 combination therapy can induce meaningful responses in some patients. Adding CD40 may provide additional benefit. Next-generation anti-CTLA-4 antibodies, such as botensilimab, are showing promise in clinical trials. Combining botensilimab with RT and/or CD40 agonist may offer additional benefits for challenging tumor types.

放射治疗和抗CTLA-4联合治疗可以在一些患者中诱导有意义的反应。添加CD40可以提供额外的益处。下一代抗CTLA-4抗体,如博滕西林单抗,在临床试验中显示出前景。将博滕司单抗与RT和/或CD40激动剂结合可能为具有挑战性的肿瘤类型提供额外的益处。
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引用次数: 0
Interleukin-27 tackles immunosuppression in chronic lymphocytic leukemia. 白细胞介素27治疗慢性淋巴细胞白血病的免疫抑制。
IF 7.2 2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-11-03 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2276490
Iria Fernandez Botana, Giulia Pagano, Etienne Moussay, Jerome Paggetti

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world. It is characterized by a high dependency on interactions with the surrounding immune landscape, highlighting its suitability for immune-mediated therapeutic interventions. We recently revealed that the cytokine IL-27 exerts a strong anti-tumor role in CLL through a T-cell-mediated mechanism.

慢性淋巴细胞白血病(CLL)是西方世界最常见的成人白血病。其特点是高度依赖于与周围免疫环境的相互作用,突出了其对免疫介导的治疗干预的适用性。我们最近发现,细胞因子IL-27通过T细胞介导的机制在CLL中发挥强大的抗肿瘤作用。
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引用次数: 0
Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases 免疫检查点抑制剂联合治疗与单药治疗在既往自身免疫性疾病患者中的安全性和有效性
2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-10-30 DOI: 10.1080/2162402x.2023.2261264
Pankti Reid, Sabina Sandigursky, Juhee Song, Maria A. Lopez-Olivo, Houssein Safa, Samuel Cytryn, Elizaveta Efuni, Maryam Buni, Anna Pavlick, Michelle Krogsgaard, Osama Abu-Shawer, Mehmet Altan, Jeffrey S. Weber, Osama E. Rahma, Maria E. Suarez-Almazor, Adi Diab, Noha Abdel-Wahab
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引用次数: 0
Driver mutations in GNAQ and GNA11 genes as potential targets for precision immunotherapy in uveal melanoma patients GNAQ和GNA11基因驱动突变作为葡萄膜黑色素瘤患者精确免疫治疗的潜在靶点
2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-10-24 DOI: 10.1080/2162402x.2023.2261278
Sandra García-Mulero, Roberto Fornelino, Marco Punta, Stefano Lise, Mar Varela, Luis P. del Carpio, Rafael Moreno, Marcel Costa-García, Dietmar Rieder, Zlatko Trajanoski, Alena Gros, Ramón Alemany, Josep María Piulats, Rebeca Sanz-Pamplona
Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (amino acid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and does not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data from primary uveal tumors were collected from the TCGA-UM dataset (n = 80) and used to assess the immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations using a variety of tools and HLA type information. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA than GNAQ/11 Q209P. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000 G databases whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed a higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Finally, samples carrying Q209L had a higher immune-reactive phenotype. Regarding cancer risk, seven HLA genotypes with low Q209L affinity show higher frequency in uveal melanoma patients than in the general population. However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.
葡萄膜黑色素瘤(Uveal melanoma, UM)是成人最常见的眼部恶性肿瘤。近95%的UM患者携带同源基因GNAQ(氨基酸变化Q209L/Q209P)和GNA11(氨基酸变化Q209L)互异突变。UM位于免疫抑制器官中,不受免疫编辑。因此,我们假设GNAQ/11基因的驱动突变可以被免疫系统识别。从TCGA-UM数据集中收集原发性葡萄膜肿瘤的基因组和转录组学数据(n = 80),并使用各种工具和HLA类型信息评估GNAQ/GNA11 Q209L/Q209P突变的免疫原性潜力。所有预测工具均显示GNAQ/11 Q209L与HLA的结合强于GNAQ/11 Q209P。免疫原性分析显示,在1000个G数据库中,Q209L可能在73%以上的个体中出现,而Q209P预计仅在24%的个体中出现。GNAQ/ 11q209l显示hla - 1分子呈现的可能性高于几乎所有分析的驱动突变。最后,携带Q209L的样本具有更高的免疫反应表型。在癌症风险方面,7种Q209L亲和力较低的HLA基因型在葡萄膜黑色素瘤患者中的出现频率高于普通人群。然而,没有发现任何HLA基因型与生存率之间的明确关联。结果表明,GNAQ/11 Q209L变体具有很高的潜在免疫原性,可以产生新的治疗工具来治疗UM,如新抗原疫苗接种。
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引用次数: 0
Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues. T细胞库在非小细胞肺癌肿瘤、肿瘤边缘、邻近和远端肺组织中的空间异质性。
IF 7.2 2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-10-20 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2233399
Qikang Hu, Meredith L Frank, Yang Gao, Liyan Ji, Muyun Peng, Chen Chen, Bin Wang, Yan Hu, Zeyu Wu, Jina Li, Lu Shu, Qiongzhi He, Yingqian Zhang, Xuefeng Xia, Jianjun Zhang, Xin Yi, Alexandre Reuben, Fenglei Yu

Background: A better understanding of T cells in lung cancer and their distribution across tumor-adjacent lungs and peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients.

Methods: Here, we performed CDR3β TCR sequencing of 136 samples from 20 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumors, tumor edges (<1 cm from tumor), as well as adjacent lungs 1 cm, 2 cm, 5 cm, and 10 cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4, and CD8 expression was assessed using immunohistochemical staining, and genomic features were derived by targeted sequencing of 1,021 cancer-related genes. Multiplex immunohistochemistry against PD-1, CTLA4, LAG3, and TIM3 was performed on four patients to assess T cell exhaustion.

Results: Our study reveals a decreasing gradient in TIL Tumor Infiltrating Lymphocytes homology with tumor edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression.

Conclusions: Exclusion in T exhaustion cells at play across the lungs of patients with NSCLC may potentially be the mechanism for lung cancer occurrence.

背景:需要更好地了解癌症中的T细胞及其在肿瘤邻近肺和外周血中的分布,以提高免疫疗法对癌症患者的疗效并最大限度地减少其毒性。方法:我们对20例早期NSCLC患者的136份样本进行了CDR3βTCR测序,肿瘤边缘(结果:我们的研究显示,TIL肿瘤浸润淋巴细胞与肿瘤边缘、邻近肺部和外周血的同源性呈下降梯度,但在邻近肺部本身没有明显的距离相关的T细胞运输模式。此外,我们还显示,在T细胞克隆性和PD-L1表达较高的区域,病原体特异性TCR降低NSCLC患者肺部的衰竭细胞可能是肺癌癌症发生的潜在机制。
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引用次数: 0
CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis. CD4+ T细胞来源的IL-22通过促进血管生成促进肝转移。
IF 7.2 2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-10-20 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2269634
Tao Zhang, Ramez Wahib, Dimitra E Zazara, Jöran Lücke, Ahmad Mustafa Shiri, Jan Kempski, Lilan Zhao, Theodora Agalioti, Andres Pablo Machicote, Olympia Giannou, Ioannis Belios, Rongrong Jia, Siwen Zhang, Joseph Tintelnot, Hannes Seese, Julia Kristin Grass, Baris Mercanoglu, Louisa Stern, Pasquale Scognamiglio, Mohammad Fard-Aghaie, Philipp Seeger, Jonas Wakker, Marius Kemper, Benjamin Brunswig, Anna Duprée, Panagis M Lykoudis, Anastasia Pikouli, Emmanouil Giorgakis, Pablo Stringa, Natalia Lausada, Maria Virginia Gentilini, Gabriel E Gondolesi, Kai Bachmann, Philipp Busch, Rainer Grotelüschen, Ioannis C Maroulis, Petra C Arck, Ryosuke Nakano, Angus W Thomson, Tarik Ghadban, Michael Tachezy, Nathaniel Melling, Eike-Gert Achilles, Victor G Puelles, Felix Nickel, Thilo Hackert, Oliver Mann, Jakob R Izbicki, Jun Li, Nicola Gagliani, Samuel Huber, Anastasios D Giannou

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

转移是一种与癌症相关的全身性疾病,是癌症患者死亡率最高的原因。有趣的是,免疫系统和癌症细胞之间的相互作用似乎在靶器官转移形成中起着关键作用。然而,人们对这个复杂的网络只了解了一部分。我们之前发现,由组织驻留的iNKT17细胞产生的IL-22促进癌症细胞外渗,即转移的早期步骤。基于这些数据,我们旨在解读IL-22在转移形成的最后一步中的作用。我们发现IL-22水平在人和小鼠的既定转移部位都增加了。我们还发现,Th22细胞是IL-22在已建立的转移部位的关键来源,CD4+T细胞中IL-22的缺失对肝转移的形成具有保护作用。因此,在转移形成的建立中给予小鼠IL-22中和抗体显著降低了小鼠模型中的转移负担。从机制上讲,产生IL-22的Th22细胞促进了已建立的转移部位的血管生成。总之,我们的研究结果强调,IL-22在晚期转移形成中同样重要,因此,将其确定为已确定转移的新治疗靶点。
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引用次数: 0
PD-L1 (CD274) promoter hypomethylation predicts immunotherapy response in metastatic urothelial carcinoma. PD-L1(CD274)启动子低甲基化预测转移性尿路上皮癌的免疫治疗反应。
IF 7.2 2区 医学 Q1 IMMUNOLOGY Pub Date : 2023-10-19 eCollection Date: 2023-01-01 DOI: 10.1080/2162402X.2023.2267744
Niklas Klümper, Lennert Wüst, Jonas Saal, Damian J Ralser, Romina Zarbl, Jonas Jarczyk, Johannes Breyer, Danijel Sikic, Bernd Wullich, Christian Bolenz, Florian Roghmann, Michael Hölzel, Manuel Ritter, Sebastian Strieth, Arndt Hartmann, Philipp Erben, Ralph M Wirtz, Jennifer Landsberg, Dimo Dietrich, Markus Eckstein

PD-L1 status assessed by immunohistochemistry (IHC) has failed to reliably predict outcomes for patients with metastatic urothelial carcinoma (mUC) on immune checkpoint blockade (ICB). PD-L1 promoter methylation is an epigenetic mechanism that has been shown to regulate PD-L1 mRNA expression in various malignancies. The aim of our present study was to evaluate the predictive potential of PD-L1 promoter methylation status (mPD-L1) in ICB-treated mUC compared to conventional IHC-based PD-L1 assessment. We quantified mPD-L1 in formalin-fixed and paraffin-embedded tissue sections using an established quantitative methylation-specific PCR assay (qMSP) in a well-characterized multicenter ICB-treated cohort comprising N = 107 patients with mUC. Additionally, PD-L1 protein expression in tumor tissues was assessed using regulatory approved IHC protocols. The effect of pharmacological hypomethylation by the DNA methyltransferase inhibitor decitabine in combination with interferon-γ stimulation in urothelial carcinoma cell lines was investigated by IHC and FACS. mPD-L1 hypomethylation predicted objective response rate at the first staging on ICB. Patients with tumors categorized as PD-L1 hypomethylated (lower quartile) showed significantly prolonged progression-free (PFS) and overall survival (OS) after ICB initiation. In contrast, PD-L1 protein expression status neither correlated with response nor survival. In multivariable Cox regression analyses, PD-L1 promoter hypermethylation remained an independent predictor of unfavorable PFS and OS. In urothelial carcinoma cell lines, pharmacological demethylation led to an upregulation of membranous PD-L1 expression and an enhanced inducibility of PD-L1 expression by interferon γ. Hypomethylation of the PD-L1 promoter is a promising predictive biomarker for response to ICB in patients with mUC.

免疫组织化学(IHC)评估的PD-L1状态未能可靠预测免疫检查点阻断(ICB)治疗转移性尿路上皮癌(mUC)患者的结果。PD-L1启动子甲基化是一种表观遗传学机制,已被证明在各种恶性肿瘤中调节PD-L1 mRNA表达。我们本研究的目的是评估与传统的基于IHC的PD-L1评估相比,ICB治疗的mUC中PD-L1启动子甲基化状态(mPD-L1)的预测潜力。我们在福尔马林固定和石蜡包埋的组织切片中使用已建立的定量甲基化特异性PCR测定(qMSP)对mPD-L1进行了定量,该测定在一个具有良好特征的多中心ICB治疗队列中进行,该队列包括N = 107例mUC患者。此外,使用监管批准的IHC方案评估肿瘤组织中PD-L1蛋白的表达。通过IHC和FACS研究了DNA甲基转移酶抑制剂地西他滨联合干扰素-γ刺激对尿路上皮癌细胞系的药理学低甲基化作用。mPD-L1低甲基化预测了ICB第一阶段的客观反应率。被归类为PD-L1低甲基化(下四分位数)的肿瘤患者在ICB启动后显示出显著延长的无进展(PFS)和总生存期(OS)。相反,PD-L1蛋白表达状态与反应和存活率无关。在多变量Cox回归分析中,PD-L1启动子高甲基化仍然是不利PFS和OS的独立预测因素。在尿路上皮癌细胞系中,药物去甲基化导致膜状PD-L1表达上调,并增强干扰素γ对PD-L1表达的诱导性。PD-L1启动子的低甲基化是mUC患者对ICB反应的一种有前途的预测性生物标志物。
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引用次数: 0
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