缺氧诱导的lncRNA与肿瘤免疫逃逸

缺氧和免疫逃逸是肿瘤的两大特征,缺氧是促进肿瘤发生免疫逃逸的重要因素。近年来的研究结果表明,缺氧诱导的长链 非编码RNA（HIL）是介导缺氧促进免疫逃逸的关键因子,是肿瘤诊断、治疗和预后评估的潜在标志物,具有较好的研究和临床转化价 值,有望成为肿瘤免疫治疗的潜在靶点。本文综述了HIL在肿瘤发生发展及预后中最新的研究进展,讨论了HIL通过诱导上皮间质转 化发生、血管生成、肿瘤干细胞形成、糖酵解、免疫细胞浸润、免疫因子释放、干扰抗原提呈机制和免疫检查点表达上调等多种机制诱导 肿瘤发生免疫逃逸,探讨双靶向HIL与免疫检查点的联合肿瘤治疗新策略的可能性及临床意义,分析了HIL领域中关于普适性和组织 特异性关键HIL及其调控肿瘤免疫机制的鉴定、HIL与肿瘤免疫治疗及疗效之间关系的明确,以及肿瘤联合治疗新策略临床转化的实 现等关键问题及可能的解决办法,为实现靶向HIL与免疫检查点的肿瘤免疫治疗策略提供了理论基础。     

CAR-T疗法在治疗肿瘤免疫逃逸中的研究进展

机体内的免疫系统可以对肿瘤细胞产生免疫应答从而进一步消除肿瘤。但部分肿瘤能在宿主体内生长、转移和突变,表明其具有免疫逃逸的能力。肿瘤细胞抗原本身发生逃逸、效应细胞功能强弱、肿瘤细胞微环境等都与肿瘤的免疫逃逸密切相关。近年来,以嵌合抗原受体T（CAR-T）细胞疗法为主的免疫疗法在肿瘤的治疗领域发展迅猛,正逐渐成为治疗肿瘤的主流方向,本文对治疗肿瘤免疫逃逸中CAR-T的应对治疗策略和进展进行梳理,旨在为CAR-T疗法治疗肿瘤的下一步发展优化思路。     

依赖NKG2D的肿瘤免疫逃避

活化性受体NKG2D（natural—killer group 2,member D）和其配基在NK、γδ^＋T和CD8^＋T细胞介导的肿瘤免疫应答中扮演了重要角色。NKG2D识别肿瘤细胞表面的配体激活效应细胞,产生有效的抗肿瘤免疫应答。但是在完全具有免疫能力的机体内,表达NKG2D配基的肿瘤仍能够生长发育,因此,在患肿瘤小鼠和肿瘤病人中一定存在着依赖NKG2D的免疫逃避机制。本文就依赖于NKG2D的免疫逃避作一详细综述,主要包括：干涉NKG2D受体的免疫逃避、干涉NKG2D配基的免疫逃避、细胞因子破坏NKG2D受体和配基的免疫逃避、抑制性细胞参与NKG2D介导的免疫逃避。这些研究为抗肿瘤治疗提供了新的途径。     

PD-L1表达调控机制及其对抗肿瘤免疫反应的影响

肿瘤的发生是一个多因素、多步骤的过程.肿瘤细胞通过抑制机体的抗肿瘤免疫应答,实现免疫逃逸,促进肿瘤生长.肿瘤免疫逃逸的分子机制是肿瘤免疫研究的核心问题之一.在T细胞介导的免疫反应中,程序性死亡受体-1(programmed death receptor-1,PD-1)是关键的抑制性免疫检查点.肿瘤通过表达程序性死亡配体-1(programmed death ligand-1,PD-L1),可以增强PD-1抑制信号,促进肿瘤免疫逃逸.研究肿瘤细胞如何调节PD-L1表达,有助于阐明肿瘤发生免疫逃逸的分子机制.近年来的研究发现,肿瘤细胞在基因转录、转录后调节以及蛋白翻译后修饰等多个环节对PD-L1表达进行调节,并且通过调控PD-L1的表达影响抗肿瘤免疫反应.这些研究为肿瘤免疫治疗提供了新的靶点.     

Arginase 2 is expressed by human lung cancer, but it neither induces immune suppression, nor affects disease progression

In human prostate cancer, Arginase 2 (ARG2) and nitric oxide synthase (NOS) are concomitantly expressed by tumor cells, and induce tumor immune escape via peroxynitrite-dependent Tyrosine nitrosylation. Since there were no data regarding this immune suppressive mechanism in other tumor types, and an evaluation of its clinical relevance in human tumors had still to be provided, we have investigated presence and clinical relevance of ARG2 and NOS expression in lung cancer. No evidence of NOS expression was found, no significant NOS enzymatic activity was detected. Instead, ARG2 protein was expressed by tumor cells. In a cohort of 120 patients, the amount of ARG2-positive tumor cells was significantly higher in small cell lung cancers (SCLC) than in non-small cell lung cancers (NSCLC). Large cell undifferentiated carcinomas had twice ARG2 than the other NSCLC subtypes. ARG2 expression was increased in Grade 3 tumors, as compared to Grades 1 and 2. However, no relationship was found with tumor size and stage, and with patient survival. Indeed, the enzyme was active, since the Arginine catabolite Ornithine was produced, but Arginine depletion was not attained. In addition, nitrotyrosine was not found in tumor tissue. Accordingly, when tumor cells isolated from lung cancer were incubated with activated autologous T cells, no inhibition of proliferation was detected. Our results indicate that ARG2 is expressed in lung cancer, but it does not induce tumor immune escape and does not affect disease progression, most probably due to the lack of concomitant NOS expression.     

PD-1/PD-L1介导的肿瘤免疫逃逸在肿瘤微环境中的研究进展

肿瘤免疫逃逸在肿瘤的发生发展中起重要作用。近年来,作为肿瘤免疫逃逸的众多机制之一的免疫抑制,也成为了研究的热点。PD-1/PD-L1信号传导途径是肿瘤免疫抑制的重要组成部分,具有抑制T淋巴细胞的活化和增强肿瘤细胞免疫耐受的作用,从而达到肿瘤免疫逃逸。因此,靶向PD-1/PD-L1途径是癌症治疗的重要策略,本文总结了PD-1/PD-L1信号通路在肿瘤微环境中的调控机制及其在介导肿瘤逃逸中的作用。     

NKG2D ligand expression in pediatric brain tumors

Adult brain tumors establish an immunosuppressive tumor microenvironment as a modality of immune escape, with several immunotherapies designed to overcome this barrier. However, the relationship between tumor cells and immune cells in pediatric brain tumor patients is not as well-defined. In this study, we sought to determine whether the model of immune escape observed in adult brain tumors is reflected in patients with pediatric brain tumors by evaluating NKG2D ligand expression on tissue microarrays created from patients with a variety of childhood brain tumor diagnoses, and infiltration of Natural Killer and myeloid cells. We noted a disparity between mRNA and protein expression for the 8 known NKG2D ligands. Surprisingly, high-grade gliomas did not have increased NKG2D ligand expression compared to normal adjacent brain tissue, nor did they have significant myeloid or NK cell infiltration. These data suggest that pediatric brain tumors have reduced NK cell-mediated immune surveillance, and a less immunosuppressive tumor microenvironment as compared to their adult counterparts. These data indicate that therapies aimed to improve NK cell trafficking and functions in pediatric brain tumors may have a greater impact on anti-tumor immune responses and patient survival, with fewer obstacles to overcome.     

The role of immune surveillance in malignant transformation of benign salivary gland tumors

Pleomorphic adenoma (PA), the most common salivary gland tumor, is a benign tumor that carries a risk of malignant transformation to various histologies of carcinoma ex pleomorphic adenoma (CA exPA). Recently, genomic analyses have provided deeper insights into the molecular biology of salivary gland cancers. However, the molecular processes that underlie the progression from PA to CA exPA are largely unknown. In this study, we used RNAseq data from CA ex PA of myoepithelial (n = 24) or salivary duct histology (n = 6), de novo myoepithelial carcinoma (n = 16) and de novo salivary duct carcinoma (n = 10), and compared their constituent immune tumor microenvironments. We found that increasing levels of immune infiltration and activation were associated with a generally lower probability of cancer developing ex-PA, suggesting that immune surveillance may constrain the malignant transformation of benign salivary tumors. More immunologically infiltrated tumors were more likely to have developed de novo. Taken together, these data suggest a role for tumor escape from immune surveillance in the development of CA exPA. The immune-cold microenvironments of CA ex PA tumors may in part explain their more aggressive clinical behavior.     

肿瘤免疫微环境中的NK细胞及免疫治疗

自然杀伤（NK）细胞是一类具有强大抗肿瘤功能的固有淋巴细胞,能够快速识别和杀伤肿瘤细胞,其功能受活化性受体和抑制性受体的多种信号所调控。但是,肿瘤浸润NK细胞的杀伤功能由于免疫抑制性肿瘤微环境而失调,甚至会促进肿瘤细胞的免疫逃逸,导致多种免疫疗法临床治疗的效果不佳。肿瘤细胞上调表达抑制性配体、肿瘤微环境中大量抑炎因子及异常的低氧、低pH等,都诱导肿瘤浸润NK细胞杀伤功能受损。近年来,关于肿瘤微环境与肿瘤浸润NK细胞的研究正处于肿瘤免疫领域的前沿,已经取得了很多临床研究成果。多项研究表明,肿瘤浸润NK细胞通常表现为抑制性受体上调、活化性受体下调和代谢异常等特征,基于此,研究者开发了多种针对性治疗方案,以恢复NK细胞的杀伤能力。本文在阐述NK细胞功能活化和抑制相关机制的基础上,论述了肿瘤浸润NK细胞的特征及其相应的肿瘤免疫治疗方案。     

MHC class I restricted T cells and immune surveillance against transplanted ultraviolet light-induced tumors.

Studies involving tumor escape from host immune surveillance have focused heavily on loss of major histocompatibility class I antigens as well as loss of tumour-associated antigens as possible mechanisms by which tumors escape recognition and lysis by cytolytic T cells. Examples of both phenomena are found in murine tumors induced by viruses, chemical mutagens, a spontaneous tumor mutagenized in vitro and some u.v.-induced tumors. However, evidence also exists for the escape of tumors from immune destruction without loss of major histocompatibility class I molecules or tumor antigens and additional mechanisms undoubtedly are involved in the complex phenomena of tumor progression.     

PD-1和PD-L1在肿瘤免疫逃逸中的作用机制及临床意义

随着人们对肿瘤免疫微环境的深入研究,发现肿瘤细胞的免疫逃逸是造成肿瘤进展的关键原因,其分子机制也成为肿瘤免疫治疗研究的重点问题之一。近年研究表明程序性死亡受体-1（programmed death receptor-1,PD-1）与程序性死亡配体-1（programmed death ligand-1,PD-L1）与肿瘤发生、发展有密切联系。其中,PD-1是T细胞介导免疫反应中的重要抑制性免疫检查点,肿瘤细胞通过表达PD-L1,与肿瘤浸润淋巴细胞的PD-1结合,诱导淋巴细胞的凋亡,从而抵抗淋巴细胞的杀伤作用,最终造成肿瘤发生免疫逃逸。本文对PD-1和PD-L1在肿瘤免疫逃逸中的作用机制及在肿瘤治疗中的临床意义作一综述。     

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD‐1) or programmed death‐ligand 1 (PD‐L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD‐L1 expression on tumors, tumor‐infiltrating lymphocytes, tumor‐associated macrophages, and myeloid‐derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.     

The intersection of cancer,cancer stem cells,and the immune system: therapeutic opportunities

During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma.     

肿瘤消融技术联合免疫检查点抑制剂治疗的进展

随着微创手术的广泛应用及微创技术的发展,肿瘤消融技术已成为肿瘤局部治疗的重要替代方法,肿瘤消融在其杀灭肿瘤细胞的同时将肿瘤的自身抗原释放到循环中使机体产生了免疫抗肿瘤反应,但这种作用可能不足以克服一些已经进化出免疫应答的检查点逃逸机制的肿瘤的复发及转移。临床前和临床证据表明肿瘤消融技术联合免疫检查点抑制剂可产生更强的免疫抗肿瘤反应。本文的目的是总结肿瘤消融技术联合免疫检查点抑制剂在原发及继发肿瘤治疗的现状及进展。     

Vascular endothelial growth factor (VEGF) impairs the motility and immune function of human mature dendritic cells through the VEGF receptor 2‐RhoA‐cofilin1 pathway

Dendritic cells (DCs) are potent and specialized antigen presenting cells, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses against cancer. Tumor cells can escape from immune attack by secreting suppressive cytokines that solely or cooperatively impair the immune function of DCs. However, the underlying mechanisms are not fully defined. Vascular endothelial growth factor (VEGF) has been identified as a major cytokine in the tumor microenvironment. To elucidate the effects of VEGF on the motility and immune function of mature DCs (mDCs), the cells were treated with 50 ng/mL VEGF and investigated by proteomics and molecular biological technologies. The results showed that VEGF can impair the migration capacity and immune function of mDCs through the RhoA‐cofilin1 pathway mediated by the VEGF receptor 2, suggesting impaired motility of mDCs by VEGF is one of the aspects of immune escape mechanisms of tumors. It is clinically important to understand the biological behavior of DCs and the immune escape mechanisms of tumor as well as how to improve the efficiency of antitumor therapy based on DCs.     

CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo

The suppressive activity of regulatory T cells (Treg) has been implicated as an important factor limiting immune mediated destruction of tumor cells. However, not much is known about the presence and function of Treg within tumors. Here we show in a syngeneic murine glioma model a time-dependent accumulation of CD4+FoxP3+ Treg in brain tumors. Further analysis revealed a time-dependent upregulation of CD25, CTLA-4, GITR and CXCR4 on intratumoral CD4+FoxP3+ Treg during tumor growth. Moreover, freshly isolated intratumoral Treg were highly suppressive when tested directly ex vivo. Treatment with anti-CD25 monoclonal antibodies (mAbs) significantly reduced the number of these highly suppressive CD4+FoxP3+ cells within the growing tumor and provoked a CD4 and CD8 T cell dependent destruction of the glioma cells. Combining Treg depletion with administration of blocking CTLA-4 mAbs further boosted glioma-specific CD4+ and CD8+ effector T cells as well as antiglioma IgG2a antibody titers resulting in complete tumor eradication without any signs of autoimmunity. These data illustrate that intratumoral accumulation and activation of CD4+FoxP3+ Treg act as a dominant immune escape mechanism for gliomas and underline the importance of controlling tumor-infiltrating Treg in glioma immunotherapy.     

Tumor metabolism as modulator of immune response and tumor progression

About a century ago Otto Warburg observed that tumor cells exhibited increased glycolysis despite the presence of oxygen and stated this metabolic shift to glycolysis as the origin of cancer cell. In the meantime it has become clear, that the altered glucose metabolism is only one piece of the tumor metabolome puzzle. In addition, amino acid, lipid and adenosine metabolism are adapted to fulfill the tumors needs for energy and generation of building blocks such as lipids and nucleotides for new cell structures. The altered tumor metabolism leads to accumulation of specific metabolites in the tumor environment and creates a favorable milieu for tumor growth, progression and metastasis. These tumor-derived metabolites are important players in immune escape mechanisms beside other known factors such as cytokines, chemokines and growth factors. A variety of metabolites re-educate immune cells and prevent an effective immune response against tumor cells. Furthermore, tumor infiltrating immune cells support tumor growth by the secretion of cytokines, growth factors and other metabolic determinants. Hence, a complex interplay of tumor metabolites, cytokines and stromal factors is active in tumors and facilitates their establishment and growth. Pharmacological blockade of tumor metabolites could overcome some limitations of cancer treatment and rescue the endogenous immune response against tumor cells.     

Immune microenvironment profiles of tumor immune equilibrium and immune escape states of mouse sarcoma

Cancer immunoediting consists of three distinct phases: elimination, equilibrium and escape. Here, for the first time, we investigated the immune microenvironment profiles of tumor immune equilibrium and immune escape states in 3′-methylcholanthrene-induced murine sarcoma model. Our study indicates the relative balance of monocytic MDSCs and antitumor immunity cells (especially CTLs, NK cells and γδT cells) may involve in maintaining tumor cells in a state of immune-mediated dormancy. In addition, high percentages of Treg cells and PMN-MDSCs are associated with the tumor immune escape state – mice with progressing sarcomas. In summary, the relative balance of immune effector cells and suppressive populations in the tumor microenvironment may involve in determining the fate of tumors.     

肿瘤免疫逃逸机制的研究新进展

目的：探讨肿瘤免疫逃逸的机制,指导肿瘤治疗理论研究。方法：应用NCBI的PubMed文献数据库,以＂肿瘤免疫逃逸、T淋巴细胞、髓源性抑制性细胞,免疫抑制因子,胸腺萎缩＂等为关键词,检索2005至2010相关文献。最后纳入分析40余篇文献。结果：肿瘤细胞可通过多种途径逃避机体免疫系统的监视,包括肿瘤对T淋巴细胞的功能抑制,诱导分化出免疫抑制细胞如髓源性抑制细胞,调节性T细胞等。同时肿瘤可导致免疫抑制因子如IL-10,IL-4、TGF-β、VEGF、IDO、COX-2的上调。促进免疫器官胸腺的萎缩。结论：肿瘤免疫逃避机制十分复杂,深刻认识肿瘤免疫逃逸机制,有助于肿瘤防治研究的深入。     

肿瘤免疫逃逸机制的研究新进展

目的:探讨肿瘤免疫逃逸的机制,指导肿瘤治疗理论研究。方法:应用NCBI的PubMed文献数据库,以"肿瘤免疫逃逸、T淋巴细胞、髓源性抑制性细胞,免疫抑制因子,胸腺萎缩"等为关键词,检索2005至2010相关文献。最后纳入分析40余篇文献。结果:肿瘤细胞可通过多种途径逃避机体免疫系统的监视,包括肿瘤对T淋巴细胞的功能抑制,诱导分化出免疫抑制细胞如髓源性抑制细胞,调节性T细胞等。同时肿瘤可导致免疫抑制因子如IL-10,IL-4、TGF-β、VEGF、IDO、COX-2的上调。促进免疫器官胸腺的萎缩。结论:肿瘤免疫逃避机制十分复杂,深刻认识肿瘤免疫逃逸机制,有助于肿瘤防治研究的深入。