调节性T细胞与妇科恶性肿瘤免疫研究进展

调节性T细胞(regulatory T cell, Treg)是一群具有抑制其他免疫细胞功能的负调控细胞,包括CD4+ Treg、CD8+ Treg、自然杀伤T细胞(natural killer T cell,NKT)和双阴性Treg(double negative Treg,DN Treg)细胞等4大类。Treg细胞在妇科恶性肿瘤免疫抑制及逃逸机制中起重要作用。肿瘤可诱导生成特异性Treg细胞,CD4+ CD25+ T细胞向Treg细胞的转化可能是引起肿瘤微环境中Treg细胞数量增多的原因。本文就CD4+ CD25+ Treg细胞与妇科恶性肿瘤免疫抑制及逃逸之间的关系进行综述。     

肝癌小鼠脾脏免疫细胞的变化及其意义

目的:观察小鼠H22细胞原位种植性肝癌模型中,脾脏正性免疫细胞和负性免疫细胞比例的变化,并且观察脾脏切除后外周血和肿瘤组织免疫细胞比例的变化以及对肿瘤生长的影响。方法:建立小鼠H22细胞原位种植性肝癌模型,在荷瘤的不同时期,用流式细胞术检测脾脏中负性免疫细胞（MDSC、Treg）和正性免疫细胞（总CD3+T细胞、CD4+T细胞、CD8+T细胞、NK细胞、NKT细胞）比例的变化。荷瘤1 w后切除脾脏,用流式细胞术检测外周血及肿瘤组织中免疫细胞比例的变化,并比较切脾前后肿瘤重量、腹水量、荷瘤小鼠生存期的变化。 结果:荷瘤小鼠脾脏MDSC细胞的比例一直高于正常组;Treg细胞在荷瘤2 w时显著升高;总CD3+T细胞和CD4+T细胞在荷瘤1 w时显著升高,2 w时显著下降;CD8+T细胞在荷瘤2 w时明显下降;NK细胞在荷瘤3 w时明显下降;NKT细胞无显著变化。脾脏切除后外周血和肿瘤组织MDSC的比例下降,CD8+T细胞的比例升高;肿瘤重量和荷瘤小鼠生存期无显著变化,腹水量在荷瘤2 w时显著减少,腹水发生率明显降低。 结论:小鼠肝脏种植H22细胞株后,脾脏中正性免疫细胞的比例下降,负性免疫细胞的比例升高,脾脏的负性免疫状态逐渐占主导地位,从而促进了肝癌的发展。     

SLAMF7-SLAMF7信号通路在肿瘤进展中的作用及相关机制CSCD

信号淋巴细胞激活分子成员7(SLAMF7)不仅表达于多种肿瘤细胞表面,也表达于众多免疫细胞中,如自然杀伤细胞、CD4+T细胞、CD8+T细胞、B细胞、树突状细胞、单核/巨噬细胞等,并参与调控肿瘤微环境中肿瘤细胞及免疫细胞的增殖、黏附、生长及分化,最终影响着免疫细胞的抗肿瘤作用。本文将对SLAMF7调控免疫细胞抑制肿瘤细胞功能的研究现状进行综述。     

CD4~+ CD25~+调节性T细胞及其在肿瘤免疫治疗中的意义

CD4+CD25+调节性T细胞是具有独特免疫调节功能的T细胞亚群。近年来研究发现各种恶性肿瘤患者外周血及肿瘤环境中该细胞比例增加,去除CD4+CD25+调节性T细胞或封闭其抑制功能可以增强抗肿瘤免疫反应。CD4+CD25+调节性T细胞成为肿瘤免疫治疗的新靶点。     

肿瘤患者外周血调节性T细胞的检测及临床意义

目的:研究肿瘤患者外周血调节性T细胞水平的变化并探讨其临床意义,旨在了解肿瘤患者的免疫功能改变,为肿瘤患者临床治疗及判断预后提供依据。方法:采用流式细胞仪对40例肿瘤患者及40例正常人外周血CD4+CD25+T细胞、CD4+CD25highT细胞及CD4+CD25+Foxp3+Treg细胞水平进行检测。结果:肿瘤患者外周血中CD4+CD25+T细胞和CD4+CD25highT细胞高于正常对照组(P<0.05);CD4+CD25+Foxp3+调节性T细胞亦明显高于对照组(P<0.01)。结论:肿瘤患者细胞免疫功能明显异常,CD4+CD25+Foxp3+调节性T细胞增多可能是肿瘤患者免疫功能受抑的重要原因之一;调节性T细胞水平检测在评价肿瘤患者疗效及判断预后方面具有一定的临床价值。     

CD+4CD+25Foxp+3调节性T细胞在T细胞非霍奇金淋巴瘤中的研究进展

 CD+4 CD+25 调节性T细胞（CD+4 CD+25 Treg）是一个具有独特免疫调节功能的T细胞亚群, 天然的CD+4 CD+25 Treg起源于胸腺,获得性CD+4 CD+25 Treg可在外周由CD+4 CD-25 T细胞诱导产生,其分子表面表达特异性的转录抑制因子Foxp3,又可表达CD4、CD25、CTLA-4 （CD152） 、GITR等膜分子,主要功能具有免疫抑制性和免疫无能性。近年来研究发现,其在非霍奇金淋巴瘤（NHL）中存在表达异常,某些NHL外周血中或瘤内均存在CD+4 CD+25 Treg表达升高,且有研究表明其表达量随肿瘤增长和分期而增加。增加的CD+4 CD+25 Treg可加速肿瘤生长及再发,且可抑制自身效应性T细胞（CD+4 T／CD+8 T）功能,在肿瘤免疫逃逸机制中发挥一定作用。文章就CD+4 CD+25 Foxp3+调节性T细胞在T细胞非霍奇金淋巴瘤（T-NHL）（主要为皮肤T细胞淋巴瘤及成年人T细胞淋巴瘤）中的研究进展进行综述。     

调节性T细胞与肿瘤

调节性T（regulatory T, Treg）细胞是一群具有抑制其他免疫细胞功能的负调控细胞，包括CD4+ Treg、CD8+ Treg、NKT Treg 和双阴性（double negative，DN）Treg细胞等四大类。研究显示，肿瘤微环境中Treg细胞数量升高，且这些升高的 Treg细胞能抑制抗肿瘤免疫、降低肿瘤免     

基于肿瘤免疫微环境的弥漫大Ｂ细胞淋巴瘤预后分析

目的∶本研究探讨弥漫大B细胞淋巴瘤（difise Lrge B-ellmphama,DLBCL）免疫相关信号通路的活化及免疫细胞浸润模式,分析肿瘤免疫微环境与DLBCL.预后的关系。方法∶基于GEO数据库提取 DLBCL相关数据集的基因表达数据,分析16条免疫相关信号通路富集水平及27种免疫细胞浸润水平与患者预后的关系,并比较ABC亚型和GCB亚型DLBCL通路富集水平和免疫细胞浸润水平的差异。结果;数据集生存分析结果显示,适应性免疫系统通路、淋巴细胞活化通路、MHC Ⅱ类抗原呈递信号通路、I型干扰素信号通路、Ⅱ型干扰素信号通路、T17细胞分化信号通路、T细胞受体信号通路以及细胞黏附信号通路富集分数高的患者预后较好,其中I型干扰素信号通路在 GCB 亚型中显著富集。CD4+T淋巴细胞、CD4+效应记忆T细胞、CD4+记忆T细胞、CD8+T淋巴细胞、Thl细胞、活化树突状细胞在所有数据集中均表现为细胞浸润程度高者预后较好,嗜酸性粒细胞、M2 型巨噬细胞、中性粒细胞、Th2 细胞浸润程度高者则预后不良;中性粒细胞浸润程度在ABC 亚型中显著高于 CCB 亚型。结论∶DIBCL肿瘤微环境中的免疫细胞亚群和免疫相关信号通路与预后密切相关,此结果或可为将来基于免疫微环境的 DIBCL分型提供理论基础。     

鼻咽癌组织与外周血CD4+CD25+调节性T细胞检测及临床意义

目的 通过检测鼻咽癌患者肿瘤组织及外周血中CD4+T、CD8+T、CD4+CD25T、CD4+CD25+T细胞的频数,寻找客观、全面评价鼻咽癌患者免疫状态的临床指标.方法 采用流式细胞术检测40例初诊鼻咽癌患者及10例正常时照鼻咽部组织和外周血CD4+T、CD8+T、CD4+CD25-T、CD4+CD25+T细胞比例.结果 鼻咽癌患者CD4+T细胞比例及CD4+/CD8+T比值均低于对照组(P<0.05),而CD8+T细胞两组间差异无统计学意义(P>0.05),但是CD4+/CD8+T比值在鼻咽癌组织与外周血间差异无统计学意义(P>0.05).鼻咽癌组织及外周血中CD4+CD25+T细胞比例都高于对照组(P<0.05),同时癌组织中该细胞比例远远高于外周血(P<0.05).在鼻咽癌组织中CD4+CD25+T细胞与CD8+T细胞、CD4+CDQ5-T细胞呈负相关(r分别为-0.70、-0.675,P<0.05),而在外周血中没有相关关系(P>0.05).在不同T(原发肿瘤大小)组间,T4组的鼻咽癌组织中CD4+CD25+T细胞分别高于T1、T2、T3各组(P<0.05).而在T1、T2、T3各组间差异无统计学意义(P>0.05);鼻咽癌中CD4+CD25+T细胞比例与患者有无淋巴结转移并无关系(P>0.05);鼻咽癌组织中Ⅲ+Ⅳ期组CD4+CD25+T细胞比例高于Ⅰ+Ⅱ期组(P<0.05),而在外周血中两组间差异无统计学意义(P>0.05).结论 CD4+CD25+T细胞与鼻咽癌病程进展无相关性,但是联合检测患者肿瘤组织及外周血中CD4+CD25+T细胞的频数并结合既往CD4+/CD8+T比值会全面反应患者免疫状态,为临床治疗提供依据.     

PD-1抑制剂治疗晚期肺癌的疗效及对患者外周血T淋巴细胞亚群和细 胞因子水平的影响

目的：探讨PD-1抑制剂治疗晚期肺癌患者的疗效及其对患者外周血T淋巴细胞亚群及细胞因子水平的影响。方法：选择2018年8月至2020年12月于海口医院就诊的肺癌患者50例,选取同期体检健康者50例作为对照,免疫组化法检测肺癌组织中PD-1的表达。肺癌患者均接受纳武利尤单抗（nivolumab）或帕博利珠单抗（pembrolizumab）治疗,于治疗前1天、治疗1周期结束、治疗4周期结束时进行静脉血采集,治疗4周期后进行CT或MRI检查评价肿瘤大小,将评价为完全缓解（complete response,CR）、部分缓解（partial response,PR）和疾病稳定（stable disease,SD）的患者归为免疫应答组 ,评价为疾病进展（progressive disease,PD）的患者归为免疫无反应组。评估PD-1抑制剂治疗对患者外周血中T淋巴细胞亚群（CD3+T细胞、CD4+T细胞、CD8+T细胞、CD4+/CD8+T 细胞、Treg 细胞及 Th1/Th2细胞）、NK细胞和细胞因子（IFN-γ、IL-2、IL-4和IL-5）水平的影响。结果：与对照组相比,肺癌患者外周血中CD3+T细胞、CD4+T细胞、CD4+/CD8+T细胞、Th1/Th2细胞、IFN-γ和IL-2水平明显下降,而CD8+T细胞、Treg细胞、NK细胞、IL-4和IL-5水平明显升高（均P<0.05）;与治疗前相比,治疗1周期和4周期后CD3+T细胞、CD4+T细胞和CD4+/CD8+T细胞水平明显升高,而CD8+T细胞、Treg细胞和NK细胞明显下降（均P<0.05）;治疗4周期后,40例入免疫应答组,10 例入免疫无反应组,治疗有效率为 80%。与治疗无反应组比较 ,免疫应答组血清 CD3+T 细胞、CD4+T 细胞、CD4+/CD8+T细胞水平和Th1/Th2比值明显升高,而CD8+T细胞、Treg细胞和NK细胞水平明显下降（均P<0.05）;免疫应答组患者经4个周期治疗后,与PD-L1低表达（<50%）患者（8例）比较,PD-L1高表达（≥50%）患者（32例）血清CD3+T细胞、CD4+T细胞和CD4+/CD8+T细胞水平均明显升高（均P<0.05）,而CD8+T细胞、Treg细胞和NK细胞均明显下降（均P<0.05）。结论：纳武利尤单抗或帕博利珠单抗治疗能够影响晚期肺癌患者T淋巴细胞亚群等免疫细胞分布,改善患者免疫状态。     

Immune mediators in the tumor microenvironment of prostate cancer

Prostate cancer tissue is composed of both cancer cells and host cells. The milieu of host components that compose the tumor is termed the tumor microenvironment (TME). Host cells can be those derived from the tissue in which the tumor originates (e.g., fibroblasts and endothelial cells) or those recruited, through chemotactic or other factors,to the tumor (e.g., circulating immune cells). Some immune cells are key players in the TME and represent a large proportion of non-tumor cells found within the tumor. Immune cells can have both anti-tumor and pro-tumor activity.In addition, crosstalk between prostate cancer cells and immune cells affects immune cell functions. In this review,we focus on immune cells and cytokines that contribute to tumor progression. We discuss T-regulatory and T helper 17 cells and macrophages as key modulators in prostate cancer progression. In addition, we discuss the roles of interleukin-6 and receptor activator of nuclear factor kappa-B ligand in modulating prostate cancer progression. This review highlights the concept that immune cells and cytokines offer a potentially promising target for prostate cancer therapy.     

Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses

Emerging evidence has unveiled a critical role for immunological parameters in predicting tumor prognosis and clinical responses to anticancer therapeutics. On the other hand, responsiveness to anticancer drugs greatly modifies the repertoires, phenotypes, and immunogenicity of tumor-infiltrating immune cells, serving as a critical factor to regulate tumorigenic activities and the emergence of therapy-resistant phenotypes. Tumor-associated immune functions are influenced by distinct or overlapping sets of therapeutic modalities, such as cytotoxic chemotherapy, radiotherapy, or molecular-targeted therapy, and various anticancer modalities have unique properties to influence the mode of cross-talk between tumor cells and immune cells in tumor microenvironments. Thus, it is critical to understand precise molecular machineries whereby each anticancer strategy has a distinct or overlapping role in regulating the dynamism of reciprocal communication between tumor and immune cells in tumor microenvironments. Such an understanding will open new therapeutic opportunities by harnessing the immune system to overcome resistance to conventional anticancer drugs.     

Tumor microenvironment in gastric cancers

The tumor microenvironment favors the growth and expansion of cancer cells. Many cell types are involved in the tumor microenvironment such as inflammatory cells, fibroblasts, nerves, and vascular endothelial cells. These stromal cells contribute to tumor growth by releasing various molecules to either directly activate the growth signaling in cancer cells or remodel surrounding areas. This review introduces recent advances in findings on the interactions within the tumor microenvironment such as in cancer‐associated fibroblasts (CAFs), immune cells, and endothelial cells, in particular those established in mouse gastric cancer models. In mice, myofibroblasts in the gastric stroma secrete R‐spondin and support normal gastric stem cells. Most CAFs promote tumor growth in a paracrine manner, but CAF population appears to be heterogeneous in terms of their function and origin, and include both tumor‐promoting and tumor‐restraining populations. Among immune cell populations, tumor‐associated macrophages, including M1 and M2 macrophages, and myeloid‐derived suppressor cells (MDSCs), are reported to directly or indirectly promote gastric tumorigenesis by secreting soluble factors or modulating immune responses. Endothelial cells or blood vessels not only fuel tumors with nutrients, but also interact with cancer stem cells and immune cells by secreting chemokines or cytokines, and act as a cancer niche. Understanding these interactions within the tumor microenvironment would contribute to unraveling 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。     

The tumor microenvironment and its role in promoting tumor growth

The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T(reg)) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-kappaB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.     

Inflammation,inflammatory cells and angiogenesis: decisions and indecisions

Endothelial-immune cell cross-talk goes well beyond leukocyte and lymphocyte trafficking, since immune cells are able to intimately regulate vessel formation and function. Here we review the evidence that most immune cells are capable of polarization towards a dichotomous activity either inducing or inhibiting angiogenesis. In addition to the well-known roles of tumor associated macrophages, we find that neutrophils, myeloid-derived suppressor and dendritic cells clearly have the potential for influencing tumor angiogenesis. Further, the physiological functions of NK cells suggest that these cells may also show a potentially important role in pro- or anti-angiogenesis regulation within the tumor microenvironment. At the same time many angiogenic factors influence the activity and function of immune cells that generally favor tumor survival and tolerance. Thus the immune system itself represents a major pharmaceutical target and links angiogenesis inhibition to immunotherapy.     

Immune cytolysis of murine tumor cells mediated by xenogeneic "immune" RNA

Using a quantitative assay for lymphocyte-mediated cytotoxicity, it was shown that normal, non-immune C3Hf/HeCr mouse spleen cells were converted to effector cells specifically cytotoxic to chemically induced C3H tumor cells by incubation in vitro with “immune” RNA extracted from the lymphoid organs of specifically immunized guineapigs. This response was specific for the tumor used to immunize the RNA donor. Cytotoxicity indices (CIs) at 0.30 to 0.54 were consistently obtained. Spleen cells incubated with RNA from guinea-pigs immunized with a different tumor, or with normal C3H tissue, failed to lyse the target cells. These immune responses were abrogated when the “immune” RNA was treated with RNase prior to incubation with the spleen cells. However, pre-treatment with DNase or pronase did not alter the activity of the “immune” RNA. “Immune” RNA to a second chemically induced C3H tumor mediated a cytotoxic response to that tumor (CI=0.45), but not to the first tumor. This clearly demonstrates that xenogeneic “immune” RNA mediates tumor-specific immune cytolysis, in vitro.     

Current immunotherapeutic strategies in pancreatic cancer

The immune systems of patients with newly diagnosed pancreatic cancers are functional, with T-cell responses capable of responding to tumor antigen presentation. Pancreatic tumors have been demonstrated to express tumor antigens as mutated, altered, underglycosylated and/or inappropriately overexpressed proteins. Considering these two facts, it should be possible for patients' bodies to recognize their tumors as foreign and to reject them. A number of clinical trials have been initiated to exploit this immune activation to eradicate or stabilize tumor growth. Immunotherapeutic trials include the specific testing of a variety of tumor vaccines, of cytokines as adjuvants or directed cytotoxicity, and of monoclonal antibodies to target specific molecules. This article reviews evidence for immune-cell activation and function in patients with pancreatic cancer, and evidence that pancreatic tumor cells express tumor antigens, or mutated (or altered) proteins. Nevertheless, tumors survive immune attacks by producing products that help them to circumvent effector T cells. The article thus examines complications of immune evasion by cancer cells, as well as the challenges of trying to exploit the immune system in solid tumors where tumor cell products can turn off invading immune T cells set to kill them. Finally, the article discusses the choices of a variety of clinical trials using immune modulation for patients with pancreatic cancer.     

鼻咽癌与免疫逃逸

肿瘤的免疫逃逸是癌症的一大特征,目前所知的肿瘤逃逸机制主要包括肿瘤的直接免疫逃逸和肿瘤微环境介导的免疫逃逸.鼻咽癌的发生发展与其肿瘤细胞的免疫逃逸密切相关,其中与鼻咽癌相关的肿瘤的直接免疫逃逸主要包括肿瘤细胞表面主要组织相容性复合体-Ⅰ类分子表达下降或缺失、肿瘤细胞缺乏共刺激分子以及Fas/FasL系统介导的免疫逃逸;与鼻咽癌相关的肿瘤微环境介导的免疫逃逸则包括肿瘤相关免疫抑制分子和肿瘤相关免疫抑制性细胞.研究鼻咽癌免疫逃逸的作用机制能够为其治疗及预防提供新的研究方向.     

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.