Background::Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy. Methods::Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification. Results::A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1. Conclusions::The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.

乳腺癌在肿瘤内和肿瘤间均表现出异质性，这种高度的异质性给该肿瘤的研究和治疗带来了巨大的困难。类器官是一种衍生于干细胞或器官祖细胞的新型3D实验模型，具有培养周期短、成功率高等优点。相较于传统的肿瘤细胞株模型(CCL)和患者来源的肿瘤异种移植模型(PDTX)，类器官模型能够在体外长期稳定增殖，既很好的保持了肿瘤异质性，又适用于高通量的药物筛选和基因编辑。目前，类器官技术已在胃肠道肿瘤、胰腺癌、肝癌、前列腺癌、乳腺癌等领域取得了一定的进展。本文就乳腺癌类器官的构建及其研究进展进行综述。

患者来源的肿瘤异种移植(patient-derived tumor xenografts,PDTX)模型,因其较好地保留了原代肿瘤的遗传、分子、形态结构等方面的特征,维持了肿瘤干细胞的特性,能反映患者肿瘤的遗传多样性,并且在对治疗的反应性上也与患者保持较高的一致性,现己越来越多地被应用于临床前期研究.近年来,NSG(NOD/LtSz-Prkdcscid Il2rgtml Wjl/J)、NOG(NOD.Cg-PrkdcscidIL2rgtmlSug/JicCrl)和NCG(NOD-Prkdcem26Cd52Il2rgem26Cd22/Nju)等免疫缺陷小鼠的研发成功,推动了新一代PDTX模型研究的快速发展.由于新一代PDTX模型建立所需样本量小,经过冷冻的组织与新鲜组织成瘤率无明显差异,为一些难以获取大量样本的肿瘤组织提供了研究材料.笔者对近年来PDTX模型用于个性化治疗方案的筛选制定、药物的临床前研究、肿瘤耐药机制的研究、肿瘤标志物及敏感指标的筛选、肿瘤微环境的研究以及患者预后的评估等的发展现状作一综述.

患者来源的肿瘤异种移植模型(patient-derived tumor xenograft model,PDTX模型)是指将患者的肿瘤组织直接移植到免疫缺陷的小鼠体内,依靠小鼠提供环境生长的一种异种肿瘤移植模型.PDTX模型高度保留了原代肿瘤的异质性、组织学特性、分子多样性以及微环境,为临床前药效的评估、个体化治疗方案的筛选以及生物标志和作用靶点的发现提供了有效的研发基础.PDTX模型结合临床数据、基因组图谱以及药效学数据,应用于肿瘤患者个体化治疗,可以增加药物使用的特异性,提高临床治疗成功率,带动肿瘤个体化治疗及精准医疗的发展.本文就PDTX小鼠模型的历史背景、建模影响因素、临床应用情况及其局限性进行综述.

人源性肿瘤组织异种移植(PDTX)模型是通过将患者新鲜的肿瘤组织植入免疫缺陷小鼠,依靠小鼠提供的微环境生长.此模型保留了原代肿瘤的病理生理特性、组织学和表型特征,维持了肿瘤细胞的基质和干细胞组成,可代替患者进行临床前试验研究,以便找到更加真实可靠的抗癌策略.消化系统肿瘤是发病率和死亡率极高的疾病,目前已有多项国内外实验开发了消化系统PDTX模型并用于相应肿瘤的研究.本文就PDTX模型在消化系统肿瘤研究中的最新应用成果进行综述,并讨论和展望未来肿瘤治疗的发展方向.

过去几十年间,胰腺癌常用的临床前模型是体外培养的肿瘤细胞或衍生于细胞的小鼠异种移植物,该模型存在长期离体培养引起生物学性质改变从而导致基因表达模式的改变[1]、体外培养的细胞缺失肿瘤微环境[2-5]、肿瘤细胞系传代培养不能反映不同患者之间的异质性等不足.人源性肿瘤组织异种移植(patient-derived tumor xenografts,PDTX)模型的出现弥补了上述不足.胰腺癌PDTX模型的建立是将新鲜的胰腺癌肿瘤组织移植到免疫缺陷鼠体内的过程,它保留了原发肿瘤的相似性,在相对真实的肿瘤基质微环境中生长、传代,高度保留了原始胰腺癌的异质性[6],这种相似性不仅表现在基因来源、组织结构、生物学行为上,更表现为对药物的反应具有很好的平行性和预测性.

目的 建立人源肿瘤异种移植 (patient-derived tumor xenografts,PDTX) 模型,观察模型肿瘤移植瘤的成瘤潜伏期、成瘤率、肿瘤体积、肿瘤的侵袭和转移等情况.方法 纳入2015年4～12月南京鼓楼医院胸心外科7例胸部肿瘤患者,其中男5例、女2例,年龄61～71岁.4例食管肿瘤,3例肺部肿瘤.将手术切除患者的新鲜肿瘤组织移植于NOD-Prkdcem26Il2rgem26Nju (NCG) 小鼠皮下,观察移植瘤的成瘤潜伏期、成瘤率、肿瘤体积、肿瘤的侵袭和转移情况以及病理HE染色、免疫组化,比较PDTX模型肿瘤组织与患者原发肿瘤组织病理的一致性.结果 7例 (其中1例术后病理显示良性) 患者PDTX模型中成功4例,建模成功率为66.7％,其中4例食管癌成功2例.PDTX模型保持了肿瘤细胞的分化程度、形态特征、结构特点.结论 PDTX模型的病理学及分子生物学特征与原始肿瘤保持一致,可以作为临床肿瘤患者的"替身",用于临床药效学筛选和新药研发.

精准模拟肺癌发病病理过程的动物模型是促进肺癌基础和转化研究的关键,而目前常用的皮下移植瘤模型难以体现肺脏的基质环境特征.小动物活体成像技术可客观、动态地评价肺癌的肿瘤负荷变化及转移发生情况,在此基础上建立的肺癌原位移植瘤动物模型可解决以上难题,充分体现肺癌的发病学特征.而人源性肿瘤组织异种移植(patient derived tumor xenograft,PDTX)原位模型和类器官模型也可部分体现肿瘤微环境和肿瘤细胞的异质性,均已成为该领域的重要发展方向.

肝是结直肠癌转移主要的靶器官,结直肠癌肝转移也是结直肠癌患者死亡的主要原因.近年来研究显示,结直肠癌肝转移原代肿瘤组织的异种移植(patient-derived tumor xenograft,PDTX)动物模型能较好的复制临床肿瘤患者的特征,其建模方法主要分为异种原位与异种异位种植模型.本文综述结直肠癌肝转移PDTX动物模型造模方法及其应用范围,以期为实验建模提供参考.

Objective:Pancreatic ductal adenocarcinoma cancer (PDAC) is one of the leading causes of cancer-related death worldwide.Hence,the development of effective anti-PDAC therapies is urgently required.Patient-derived xenograft (PDX) models are useful models for developing anti-cancer therapies and screening drugs for precision medicine.This review aimed to provide an updated summary of using PDX models in PDAC.Data sources:The author retrieved information from the PubMed database up to June 2019 using various combinations of search terms,including PDAC,pancreatic carcinoma,pancreatic cancer,patient-derived xenografts or PDX,and patient-derived tumor xenografts or PDTX.Study selection:Original articles and review articles relevant to the review's theme were selected.Results:PDX models are better than cell line-derived xenograft and other models.PDX models consistently demonstrate retained tumor morphology and genetic stability,are beneficial in cancer research,could enhance drug discovery and oncologic mechanism development of PDAC,allow an improved understanding of human cancer cell biology,and help guide personalized treatment.Conclusions:In this review,we outline the status and application of PDX models in both basic and pre-clinical pancreatic cancer researches.PDX model is one of the most appropriate pre-clinical tools that can improve the prognosis of patients with pancreatic cancer in the future.