LAG-3 及其抑制剂在肿瘤免疫治疗中应用的研究进展

[摘要] 淋巴细胞活化基因3（lymphocyte-activation gene 3,LAG-3）又称CD223,是一种由LAG-3 基因编码的含有498 个氨基酸的I 型穿膜蛋白,由胞外区、穿膜区和胞内区三部分组成。LAG-3 主要通过胞外区与配体结合,负向调控T淋巴细胞,避免T细胞过度激活引发自身免疫。与程序性死亡蛋白-1（programmed cell death 1,PD-1）和细胞毒性T淋巴细胞抗原4（cytotoxic T lymphocyte antigen 4,CTLA-4）一样,LAG-3 是体内重要的免疫检查点,对人体免疫系统起到平衡调控作用。肿瘤细胞通过高表达LAG-3 配体逃避机体免疫系统的监视。随着免疫检查点的研究逐渐深入,LAG-3 成为继PD-1 和CTLA-4 之后新一代的免疫治疗靶点。本文主要对LAG-3的结构、功能及其抑制剂在肿瘤免疫治疗中的应用进行综述,以期为LAG-3 的进一步研究提供参考。     

PD-1/PD-L1抑制剂联合治疗在癌症免疫治疗中的研究进展

程序性死亡蛋白-1(programmed cell death-1,PD-1)是一种免疫检查点的负性调控因子,通过与其配体PD-L1/PD-L2结合,抑制T细胞的免疫功能,而PD-1抑制剂则可恢复免疫系统的抗肿瘤作用。较其他治疗手段而言,PD-1抑制剂有显著的临床疗效,然而其仍然存在不足,即目前仍有很大一部分癌症患者对PD-1抑制剂治疗是无效的。研究表明联合治疗可改善PD-1抑制剂单药治疗的有效率。联合治疗包括联合免疫检查点抑制剂、放疗、化疗、癌症疫苗和其他癌症治疗方法。FDA已批准了PD-1抑制剂联合CTLA-4阻断剂治疗,其抗肿瘤效率与肿瘤微环境以及免疫相关因子有关,但关于免疫系统,特别是T细胞对肿瘤阳性响应率的潜在作用机制研究甚少。本文将综述免疫检查点PD-1抑制剂的临床疗效以及其影响因素、作用机制以及PD-1抑制剂联合其他治疗的研究现状。     

PD-1/PD-L1和CTLA-4免疫检查点抑制剂在小细胞肺癌中的临床研究进展

小细胞肺癌(SCLC)属于高度恶性神经内分泌癌,早期即易发生转移,确诊时60％～70％已处于广泛期,手术治疗机会小.虽然SCLC起始对含铂方案系统化疗±放疗的一线治疗高度敏感,但多数在一线治疗后短期内即出现复发与转移.尽管近30年来对SCLC治疗不断探索与研究,仍缺乏有效治疗手段,患者长期生存率极低.近年来以免疫检查点...     

免疫检查点抑制剂在恶性淋巴瘤中的应用研究进展*

免疫检查点是一类免疫抑制性分子,通过调节免疫反应的强度和广度,从而避免正常组织的损伤和破坏。近年来研究发现肿瘤细胞可通过激活免疫检查点活性,从而逃避免疫系统的监视。免疫检查点抑制剂则通过拮抗免疫检查点蛋白,促进T 细胞活化,进而产生抗肿瘤免疫效应。免疫检查点抑制剂在多种实体瘤的治疗方面已显示出良好的疗效。在淋巴瘤的治疗领域,虽然尚处于起步阶段,检查点抑制剂亦显示出良好的疗效及安全性。本文主要总结免疫检查点蛋白细胞毒性T 淋巴细胞相关抗原- 4（cytotoxic T lymphocyte associated antigen-4,CTLA- 4）、程序性死亡受体- 1（programmed death- 1,PD- 1）及其程序性死亡受体配体- 1（programmed death ligand 1,PD-L1）的生物学活性,并介绍相应抗体药物在淋巴瘤研究中的进展。      

肿瘤免疫检查点抑制剂相关的心脏毒性

随着恶性肿瘤治疗的不断发展, 免疫检查点抑制剂已应用于多种恶性肿瘤的治疗, 使患者的生存时间和生活质量有所改善, 但在应用的过程中不可避免地发生免疫相关不良反应。与化疗药物和靶向药物相同, 免疫抑制剂也会引起心血管事件, 从而影响肿瘤患者的死亡率。随着肿瘤患者生存时间的延长, 会日益成为影响这类疾病预后的关键因素。文章重点论述免疫检查点抑制剂在肿瘤治疗过程中引起的心脏毒性机制、临床表现以及未来发展方向。     

免疫检查点抑制剂在结直肠癌中的研究进展CSCD

免疫治疗是当前实体肿瘤治疗研究的新方向,而在免疫系统中发挥负性调节分子的免疫检查点在限制抗肿瘤免疫反应中起着关键作用。针对PD-1及PD-L1、CTLA-4的免疫检查点抑制剂已被开发为抗肿瘤药物进行临床研究,dMMR/MSI-H型结直肠癌对免疫检查点抑制剂具有客观反应。本文基于结直肠癌免疫分型,对免疫检查点抑制剂在结直肠癌中的治疗方案进行综述。     

免疫检查点抑制剂在软组织肉瘤中的应用：现状与展望

软组织肉瘤是一类少见的起源于间叶组织的除骨或软骨以外的恶性肿瘤,发病率低,但晚期转移患者通常缺乏有效的治疗手段,预后差,死亡率高。近年来,免疫检查点抑制剂(ICIs)在恶性肿瘤免疫治疗领域中取得了重要进展。在许多肿瘤中,ICIs有效改善了患者的预后,但在软组织肉瘤中,虽然有相关应用探索,却尚未获得高级别循证医学证据。本文总结了ICIs在软组织肉瘤临床治疗中的进展,包括ICIs单药及与其他治疗手段的联合使用,探讨了ICIs在未来软组织肉瘤治疗中的研究方向,希望为相关临床工作者提供参考。     

免疫检查点阻断剂治疗消化系统肿瘤研究进展

免疫检查点阻断剂是近年来恶性肿瘤治疗的研究热点,它们在消化系统肿瘤中有着不可忽视的地位。其中Nivolumab在延长晚期肝癌生存期方面超过了索拉非尼。Pembrolizumab在PD-L1阳性晚期食管癌有效率可达30％。然而易普利单抗（Ipilumumab）在晚期胰腺癌中并未看到明显疗效。然而更多的研究如Avelumab治疗晚期胃癌、Pembrolizumab治疗晚期食管鳞状细胞癌等正在进行研究中。     

免疫检测点抑制剂特殊安全性问题的认识及处理

近几年,美国食品药品管理局（FDA）相继批准了抗细胞毒T淋巴细胞相关抗原4（CTLA-4）和抗程序性死亡受体1（PD-1）两种免疫检测点抑制剂（ICBs）用于黑色素瘤和非小细胞肺癌的治疗。研究发现,ICBs在多种肿瘤亚型的治疗中均有效,包括小细胞肺癌、肾细胞癌、尿道上皮癌、头颈鳞状细胞癌、胃癌、肝细胞癌、卵巢癌、三阴性乳腺癌以及错配修复缺陷型直肠癌等。这些以免疫系统为靶点的药物疗效显著,但同时伴随一定的免疫相关不良事件（irAEs）或者免疫异常毒性的发生,如何管理这些毒副作用尚没有成熟的方法。本综述将对目前国内外关于ICBs免疫异常毒性的管理相关经验进行总结,以期能够给临床医师在肿瘤患者的免疫异常毒性管理工作中提供一些参考。     

Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers

Immune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.Subject terms: Gastric cancer, Oesophageal cancer     

Biomarkers for response to immune checkpoint inhibitors in gastrointestinal cancers

Gastrointestinal (GI) cancers account for a large proportion of cancer deaths worldwide and pose a major public health challenge. Immunotherapy is considered to be one of the prominent and successful approaches in cancer treatment in recent years. Among them, immune checkpoint inhibitor (ICI) therapy, has received widespread attention, and many clinical findings support the feasibility of ICIs, with sustained responses and significantly prolonged lifespan observed in a wide range of tumors. However, patients treated with ICIs have not fully benefited, and therefore, the identification and development of biomarkers for predicting ICI treatment response have received further attention and exploration. From tumor genome to molecular interactions in the tumor microenvironment, and further expanding to circulating biomarkers and patient characteristics, the exploration of biomarkers is evolving with high-throughput sequencing as well as bioinformatics. More large-scale prospective and specific studies are needed to explore biomarkers in GI cancers. In this review, we summarize the known biomarkers used in ICI therapy for GI tumors. In addition, some ICI biomarkers applied to other tumors are included to provide insights and further validation for GI tumors. Moreover, we present single-cell analysis and machine learning approaches that have emerged in recent years. Although there are no clear applications yet, it can be expected that these techniques will play an important role in the application of biomarker prediction.     

Association of KMT2C/D loss-of-function variants with response to immune checkpoint blockades in colorectal cancer

Immune checkpoint inhibitors (ICIs) have become important treatment strategies, yet responses vary among patients and predictive biomarkers are urgently needed. Mutations in KMT2C and KMT2D lead to increased levels of genomic instability. Therefore, we aimed to examine whether KMT2C/D mutations might be a predictor of immunotherapeutic efficacy. Here, we investigated the associations of KMT2C/D loss-of-function (LOF) variants with tumor mutation burden (TMB), MSI-H, PD-L1 expression, the levels of tumor-infiltrating leukocytes (TILs), and clinical response to ICIs. It was found that KMT2C/D LOF variants were associated with higher TMB. Compared with the non-LOF group, the proportion of patients with MSI-H tumors was larger in the LOF group. PD-L1 expression was higher in the LOF group only for colorectal cancer in both the Chinese and The Cancer Genome Atlas cohorts. Importantly, KMT2C/D LOF variants were associated with decreased regulatory T cells and increased levels of CD8⁺ T cells, activated NK cells, M1 macrophages, and M2 macrophages in colorectal cancer. However, there was no significant association between KMT2C/D LOF and TILs levels in other cancer types. Consistently, the results showed that KMT2C/D LOF variants were associated with prolonged overall survival only in colorectal cancer (p = 0.0485). We also presented that patients with KMT2C/D LOF mutations exhibited a better clinical response to anti-PD-1 therapy in a Chinese colorectal cancer cohort (p = 0.002). Taken together, these results suggested that KMT2C/D LOF variants could be a useful predictor for ICIs efficacy in colorectal cancer. In addition, the predictive value of KMT2C/D LOF variants was consistent with their association with TILs levels.     

抗血管生成药物联合免疫检查点抑制剂治疗恶性肿瘤的研究进展

[摘要] 肿瘤的生长需要血管的生成,不同于正常的血管,异常的肿瘤血管通过改变肿瘤微环境来抑制机体的免疫功能,从而使肿瘤发生免疫逃逸。抗血管生成治疗可以使肿瘤血管正常化,进而改善机体的免疫功能。免疫检查点抑制剂通过改变肿瘤微环境,不仅可以提高机体的免疫功能,同时也可以促进肿瘤血管的正常化。本文综述了抗血管生成治疗联合免疫检查点抑制剂治疗恶性肿瘤的理论依据以及相关的临床数据,为恶性肿瘤的治疗提供更多的治疗策略。     

BMI与免疫检查点抑制剂治疗恶性肿瘤疗效的关系

近年来,免疫检查点抑制剂(Immune checkpoint inhibitors,ICIs)的问世彻底改变了多种恶性肿瘤的治疗格局。但是并非所有患者都能从免疫治疗中获益,免疫治疗的总体有效率偏低。因此,如何筛选免疫治疗获益人群就成为目前关注的热点问题。由于肿瘤的异质性、微环境复杂性、标本可及性等因素,目前用于指导肿瘤免疫治疗的生物标记物存在一定局限性。有研究探索了临床特征对免疫检查点抑制剂疗效的预测作用,其中包括体重指数(Body mass index,BMI)。本文就BMI与恶性肿瘤免疫治疗疗效的关系进行综述。     

PET-CT在消化道肿瘤中的应用

正电子发射断层扫描(PET)是一种能够反映活体生化代谢特点的功能型显像技术,目前已被广泛应用于肺癌的临床实践。但PEI在消化道肿瘤诊断方面的应用存在着局限性,一些消化系统肿瘤对于18F-FDG显像的敏感性偏低,一些组织存在非特性摄取,这些都影响了诊断的准确率。PET-CT将形态学的CT图像和功能影像PET图像相结合,形成两种技术的优势互补,克服了PET在定位方面的不足,从而显示出在消化系统肿瘤中的应用潜力。现介绍近年来有关PET-CT在消化道肿瘤中的应用现状,并展望其研究前景。