中晚期肝癌免疫治疗现状与前景

近年来,随着肿瘤免疫治疗的飞速发展及对肝癌免疫微环境认识的不断深入,以免疫检查点抑制剂为导向的新型系统治疗越来越受到关注。除此之外还有免疫治疗方法如肿瘤疫苗、溶瘤病毒、细胞因子等传统免疫方法也在肿瘤治疗中发挥着一定作用。而基于当前的多学科协作诊疗模式,肝癌的免疫治疗更多强调联合治疗,目前免疫联合治疗的方向主要有:双免疫检查点抑制剂联合、免疫检查点联合放化疗、免疫检查点联合抗血管生成药物等。对于肝癌的免疫治疗呈现了多方案的局面。因此,本文就肝癌免疫治疗的现状与前景进行综述,以期助于临床更好的应用。     

精准肿瘤医学之实践：靶向肿瘤免疫微环境

近年来,肿瘤免疫治疗技术的发展为拓宽精准肿瘤医学领域做出了巨大贡献。免疫微环境是影响免疫治疗效果的重 要因素,其在肿瘤进展和动员抗肿瘤免疫方面都有不可忽视的作用。针对肿瘤免疫微环境的免疫性放疗、免疫检查点抑制剂、肿 瘤疫苗和免疫细胞治疗等手段已在临床研究中取得了很多成果,但其临床疗效仍有待提高。本文在介绍肿瘤免疫微环境的组成 和特征的基础上,从临床应用的角度阐述针对目前靶向肿瘤免疫微环境的治疗手段可行的优化策略。     

免疫检查点在肿瘤微环境中对DC成熟和功能调控的研究进展

[摘要] 树突状细胞（DC）是体内功能强大的抗原提呈细胞（APC）,在机体抗肿瘤免疫反应的过程中起着关键的作用。成熟DC具有激活T淋巴细胞并激活抗肿瘤免疫反应的功能,以DC为基础的抗肿瘤免疫疗法显示出良好的应用前景。免疫检查点疗法是肿瘤免疫治疗的另一强有力手段,以PD-1 和CTLA-4 为代表的免疫检查点分子在肿瘤微环境中起着免疫调节的作用,同时也对DC的成熟和功能起着重要的调控作用。肿瘤微环境中的未成熟DC和免疫检查点分子是肿瘤免疫逃逸的重要因素。因此探究免疫检查点分子对DC成熟及功能的调控机制对于抗肿瘤治疗的研究具有非常重要的意义。本文从DC的视角,阐述了肿瘤微环境中免疫检查点分子对DC成熟及功能的调控机制以及免疫检查点靶向药物联合DC疫苗应用于肿瘤临床实验的最新研究进展。     

免疫检查点抑制剂治疗肿瘤疗效的影响因素

[摘要] 肿瘤免疫治疗主要通过调节机体免疫和肿瘤之间的平衡来实现肿瘤治疗的目的,已证实对多种肿瘤具有显著的临床疗效,被认为是继手术、化疗、放疗后又一重要的治疗方法。但目前肿瘤免疫治疗尚无统一的临床应用方案,对不同的肿瘤或同一肿瘤的不同个体疗效差异巨大,严重制约其发展。既往研究发现,影响免疫检查点抑制剂反应和耐药性的关键因素包括肿瘤本身的特征（如癌症基因组、表观基因组和微环境）、肿瘤免疫表型、宿主免疫组分（全身免疫和抗肿瘤免疫）及其他的外部影响。然而,最新研究表明,肿瘤突变负荷、DNA修复基因、HLA基因型、PD-L1 表达以及肿瘤免疫抑制微环境与免疫检查点抑制剂的反应密切相关。因此,本文将从肿瘤突变负荷、DNA修复基因、HLA基因型、PD-L1 表达以及肿瘤免疫抑制微环境等5 个方面阐述其影响免疫检查点抑制剂的新机制,旨在为肿瘤的靶向治疗提供借鉴。     

锌指蛋白调控肿瘤免疫原性的作用及其机制的研究进展

寻找对肿瘤免疫原性具有关键调控作用的生物治疗靶点是抑制肿瘤免疫逃逸、提高肿瘤免疫治疗效果的关键。锌指蛋白（ZFP）通过与DNA、RNA、蛋白质的相互作用,调控肿瘤抗原的形成、肿瘤表面MHC分子及其共刺激分子的表达、损伤相关分子模式的释放等,影响肿瘤细胞的免疫原性及肿瘤微环境（TME）中免疫细胞的分布和功能,进而在调节抗肿瘤免疫应答和肿瘤免疫逃逸中发挥重要作用。近年来,临床前及临床研究探索将ZFP 相关的生物治疗方法应用于肿瘤免疫治疗,主要聚焦在免疫检查点阻断治疗、免疫细胞治疗,以及免疫治疗联合治疗策略展现出了可喜的应用前景。     

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。     

肿瘤微环境中T细胞功能障碍及其逆转策略

肿瘤微环境中T细胞功能障碍是肿瘤逃逸免疫监视的关键机制,免疫检查点分子上调导致的T细胞功能障碍是目前的研究热点。阻断免疫检查点PD-1 和CTLA-4 的临床试验在许多晚期癌症患者中显示令人鼓舞的疗效,证实肿瘤微环境中存在T细胞功能障碍以及逆转T细胞功能障碍在肿瘤治疗中的潜力。然而,这些新的免疫治疗方法只在少数癌症患者中产生持久的临床疗效,提示肿瘤微环境的异质性和复杂性。最近,单细胞水平的研究进一步阐明了肿瘤微环境中T细胞功能障碍的表型特征和临床意义,揭示表观遗传学和代谢改变是导致肿瘤微环境中T细胞功能障碍的重要机制,并提出逆转肿瘤微环境T细胞功能障碍的新方法。本文聚焦这些肿瘤微环境中T细胞功能障碍及其逆转策略的最新研究进展。     

从肿瘤微环境角度解析肿瘤免疫治疗的现状与未来

以程序性死亡因子1 (programmed death 1,PD-1)为代表的免疫检查点研究将肿瘤免疫治疗推向新的高度,其表明操纵免疫负性调控途径可以创建有效的免疫治疗方法,同时也提示肿瘤微环境在抑制或增强免疫应答中发挥重要作用.因此,剖析免疫应答与肿瘤微环境之间的相互作用机制,将有助于提供新的免疫治疗方案,并为个体化精准医疗奠定基础.本文从肿瘤微环境如何影响免疫应答的角度,总结肿瘤免疫治疗的研究进展,以期为肿瘤免疫治疗提出新的治疗策略.     

肿瘤免疫治疗疗效预测标志物的研究进展

免疫检查点抑制剂成为近年来肿瘤治疗的热点,越来越多的肿瘤患者从免疫治疗中获益。由于免疫治疗费用较高,未检测人群免疫治疗获益率仅为20%。因此,精准地选择预测性生物标志物对于肿瘤患者个体化免疫治疗至关重要。反映肿瘤免疫微环境和肿瘤细胞内在特征的生物标志物,如程序性死亡蛋白1(PD-1)及其配体PD-L1、肿瘤突变负荷、微...     

免疫检查点分子联合CAR-T细胞治疗实体肿瘤研究进展

免疫检查点分子是一组表达于免疫细胞表面,主要调控免疫细胞稳态的分子。嵌合抗原受体修饰的T细胞（CAR-T免疫疗法是通过生物技术构建表达特异性抗原的人工合成T细胞,实现肿瘤靶向杀伤的免疫治疗技术。CAR-T治疗策略已在血液肿瘤临床治疗中取得了较好的疗效,但针对实体肿瘤的CAR-T免疫治疗技术有待进一步研究完善。本文就免疫检查点分子联用CAR-T免疫疗法在实体肿瘤治疗中面临的问题及新进展进行综述。     

Au carrefour du cancer

Since the introduction of the concept of immunosurveillance in 1970 by Macfarlane Burnet and Lewis Thomas, cancer immunology has known a significant revolution and an explosion of discoveries. In this regard, manipulation of the immune system in cancer pathology has been a succession of enthusiasms and failures. Thanks to the fundamental achievements during the past three decades, non-specific passive immunotherapy of cancer has shifted to active specific immunotherapy. Thanks to the immunological arsenal (tumor peptides, dendritic cells), the clinical trials have increased but the results were not encouraging. It became clear that the escape of immunosurveillance by tumor cells is under the control of the complex tumor microenvironment and its heterogeneity, complexity and plasticity. The future of immunotherapy lies in an integrative approach to simultaneously boost the immune system and target the tumor microenvironment or combine immunotherapy with conventional treatments. In this review, we will focus on the development of cancer immunotherapy, its realities, failure and hope it raises as the fourth modality of cancer therapy.     

Role of the tumor immune microenvironment in tumor immunotherapy

Tumor immunotherapy is considered to be a novel and promising therapy for tumors and it has recently become a hot research topic. The clinical success of tumor immunotherapy has been notable, but it has been less than totally satisfactory because tumor immunotherapy has performed poorly in numerous patients although it has shown appreciable efficacy in some patients. A minority of patients demonstrate durable responses but the majority of patients do not respond to tumor immunotherapy as the tumor immune microenvironment is different in different patients for different tumor types. The success of tumor immunotherapy may be affected by the heterogeneity of the tumor immune microenvironment and its components, as these vary widely during neoplastic progression. The deepening of research and the development of technology have improved our understanding of the complexity and heterogeneity of the tumor immune microenvironment and its components, and their effects on response to tumor immunotherapy. Therefore, investigating the tumor immune microenvironment and its components and elucidating their association with tumor immunotherapy should improve the ability to study, predict and guide immunotherapeutic responsiveness, and uncover new therapeutic targets.     

精准靶向肿瘤局部的免疫治疗有可能成为治愈癌症的关键性策略

[摘要]肿瘤免疫治疗的两大重要进展：（1）在体外激活或通过基因修饰的T细胞进行体内输注;（2）通过抗体使体内被抑制的免疫细胞激活并处于相对持续作用状态。前者的基因修饰的T细胞主要是指嵌合抗原受体T（CAR-T）细胞,其对部分血液肿瘤产生了明显的疗效;后者主要指免疫检查点抗体,其对基因突变较多的肿瘤产生了明显的疗效。对于肿瘤患者而言,其肿瘤局部微环境的免疫抑制状态往往明显高于全身的免疫抑制状态。要将肿瘤局部微环境的免疫状况调整到正常或增强,全身用药时可能引发其它正常组织免疫反应过强,甚至导致严重损害,如间质性肺炎、急性心肌炎及严重肝损伤。本文通过总结肿瘤免疫微环境的形成和分类、肿瘤治疗和免疫治疗的发展历程,阐述靶向肿瘤微环境的重要性,提出了用自分泌抗体的CAR-T 细胞（白泽T细胞）高效精准靶向肿瘤局部,迅速提高肿瘤局部微环境的免疫功能,且有可能成为治愈癌症的关键策略。     

肝癌发生过程中的免疫调控：防御还是协同？

原发性肝癌是一种严重威胁我国人民身体健康的致死性疾病.以往的肝癌治疗主要针对癌细胞本身,但近年来的研究表明,免疫系统尤其是肿瘤微环境对于肝癌的发生、发展具有十分重要的调控作用.本文瞄准肝癌发生过程中免疫调控这一研究热点,对肿瘤微环境中的淋巴细胞、炎症细胞、细胞因子、趋化因子等关键要素在肝癌发生、发展过程中所发挥的重要调控作用进行初步探讨,尝试从分子和细胞水平阐述免疫系统对于肝癌发生、发展的双向调控作用,并对这些关键因子的抗肿瘤作用和潜在的药物开发前景进行评价,希望为肝癌的发病机制研究以及肝癌免疫治疗药物的研发提供一定的线索.     

弥漫型胃癌免疫治疗的现状及研究进展

免疫治疗通过激活机体自身的免疫系统对肿瘤进行攻击,是当前肿瘤治疗的热点,已在包括胃癌在内的多种恶性肿瘤中获得亮眼的成果。实体瘤由于其局部的免疫抑制性微环境为免疫治疗带来了挑战。弥漫型胃癌是胃癌中预后较差的亚型,对现有的化疗及靶向药物均不敏感,迫切需要探索新的疗法来解决这一难题。现有的研究发现,弥漫型胃癌相较于肠型胃癌具有更独特的免疫微环境。免疫治疗能否成为改善弥漫型胃癌患者预后的新治疗策略值得探究。本文重点关注了弥漫型胃癌的肿瘤微环境和免疫治疗的现状,并探讨了未来免疫治疗应用于弥漫型胃癌可能的发展方向。      

非小细胞肺癌肝转移免疫微环境及未来干预策略

肺癌是发病率和死亡率最高的恶性肿瘤，约有75%以上患者在诊断时已是晚期。肝转移是肺癌患者预后差的重要原因，约有20%的非小细胞肺癌（non-small cell lung cancer，NSCLC）患者会发生肝转移。近几年，免疫检查点抑制剂（immune checkpoint inhibitors，ICI）单药和联合治疗在晚期NSCLC患者取得了突破性进展。临床研究提示，肝转移患者亦可从ICI治疗中获益，但相较于整体人群，肝转移仍然是免疫治疗效果差的独立预后因素。因此，深入探索肝转移患者的免疫微环境，对提高这部分人群的生存预后具有重要意义。肿瘤微环境（tumor microenvironment，TME）表型是决定免疫治疗效果的关键因素，不同器官的TME具有特异性，可能是其免疫疗效差异的重要原因所在。肝脏中的多种细胞成分相互作用，构成了复杂的免疫微环境，共同参与肝脏的免疫调节。因此，聚焦于肝脏免疫微环境，并结合免疫治疗最新进展，对NSCLC肝转移的国内外研究进展进行总结，以期为确立肝转移患者治疗新策略提供线索。     

Myeloid-derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

Cancer progression is closely related to the tumor microenvironment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, signaling molecules and the extracellular matrix. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can impact the growth and evolution of cancerous cells. One of major cell components in the tumor microenvironment is myeloid-derived suppressor cells (MDSCs), which promote tumor growth and metastasis directly or indirectly by recognizing other immune cells, producing cytokines and exerting their immunosuppression functions. MDSCs have emerged as major regulators of immune responses in cancer and key targets for treating cancer. There are many limitations and side-effect in approaches of conventional cancer therapy, including radiotherapy. It has grown up to be a burgeoning field that a combination of radiotherapy and immunotherapy applied to cancer therapy. Therefore, it is fundamental to explore the immune mechanism in the process of cancer treatment. Here, we reviewed the recent progress of MDSCs in roles of the tumor microenvironment and tumor radiotherapy.     

Importance of Multiparametric Evaluation of Immune-Related T-Cell Markers in Renal-Cell Carcinoma

Immunotherapeutic therapies such as immune checkpoint inhibitors have been used in patients with renal cell carcinoma (RCC). To overcome therapeutic resistance or identify predictive markers, a comprehensive understanding of the immunologic condition in the tumor microenvironment is important. We reviewed the latest scientific findings on the comprehensive immunologic condition within the tumor microenvironment in patients with RCC and its clinical significance. The immunologic condition evaluated by 3 different methods (flow cytometry, mass cytometry, and next-generation sequencing) in 4 different cohorts of patients with RCC could commonly divide the immunologic condition into 2 or 3 groups, all of which were significantly correlated with tumor aggressiveness and patient prognosis. In particular, patients with high T-cell infiltration and immunosuppressive cells including regulatory T cells had the worst prognosis in each cohort. This classification correlated with angiogenesis and metabolism and glycolysis, and it suggested that distinct biology exists in each immunologic classification. Moreover, around 20% to 30% of the RCC patients had intratumor immunologic diversity within each individual; this might help in understanding the presence of radiologic heterogeneity for immunotherapies. In conclusion, a comprehensive understanding of the immune condition is needed for the upcoming era of novel cancer immunotherapy using not only genetic but also phenotypic and functional classifications.