髓样抑制性细胞的免疫抑制机制及其靶向治疗策略

髓样抑制性细胞(MDSC)是一组来源于未成熟髓系细胞不同分化阶段的异质性细胞群体,可通过抑制T细胞及自然杀伤(NK)细胞的活性、诱导T-regs细胞的产生、参与肿瘤血管生成等多种途径诱导免疫抑制、介导免疫耐受,在肿瘤的发展和转移方面发挥着重要的作用.运用各种方法促进MDSC分化成熟,减少其数量、抑制其功能等可能有助于肿瘤患者正常免疫状态的恢复,控制肿瘤的进展,提高其他抗肿瘤治疗的疗效.靶向MDSC已成为肿瘤免疫治疗的新思路.     

靶向髓系抑制性细胞抗肿瘤治疗策略研究进展

 髓系抑制性细胞（MDSC）来源于骨髓祖细胞和未成熟的髓细胞（IMC）,在荷瘤小鼠及肿瘤患者的骨髓、脾脏、外周血大量扩增,并募集到肿瘤组织。MDSC高表达精氨酸酶1（ARG1）、一氧化氮合酶（iNOS）、活性氧族（ROS）、过氧亚硝酸盐等介质,通过细胞接触依赖或非依赖方式诱导效应T细胞失能,或诱导调节性T细胞（Treg）等机制,抑制机体的抗肿瘤免疫功能。因此,靶向MDSC抗肿瘤策略成为研究热点,也取得了一定进展,现就当前靶向MDSC抗肿瘤免疫治疗策略及相关机制的研究进展做一简要介绍,为从事该领域的研究者提供参考。     

人体肿瘤髓系来源抑制性细胞的研究进展

髓系来源抑制性细胞(MDSC)是一群来源于髓系的异质性未分化成熟的细胞;在感染、创伤、败血症,尤其是肿瘤等病理状态下,MDSC在血液、淋巴器官、脾脏及肿瘤等组织中大量聚集;MDSC可以通过多种机制抑制肿瘤免疫,MDSC在患者外周血的数量与肿瘤的分期、负荷、远处转移及患者的预后密切相关.然而关于MDSC的研究结果大部分来自小鼠实验,由于肿瘤患者MDSC的表型比较复杂,其研究进展相对缓慢.     

髓源性抑制细胞介导的免疫抑制

肿瘤患者体内积聚的一类髓系细胞与肿瘤免疫逃逸密切相关,称为髓源性抑制细胞( MDSC).在肿瘤患者体内血液、淋巴结以及骨髓中也存在着一群MDSC,对固有免疫系统和适应性免疫系统有抑制作用,髓样抑制细胞通过多条途径发挥免疫抑制作用.通过减少患者体内MDSC的数量或抑制MDSC相关的免疫抑制作用通路,在肿瘤治疗中将是很有前...     

免疫微环境介导的肿瘤耐受机制及其靶向治疗

免疫细胞与其分泌的细胞因子相互作用共同构成免疫微环境,在肿瘤治疗耐受过程中扮演着重要角色.免疫微环境能够通过启动抗凋亡通路、介导免疫耐受、诱导上皮间质转化及形成肿瘤干细胞等途径促进肿瘤产生治疗耐受,降低肿瘤治疗疗效.肿瘤免疫治疗已成为目前肿瘤治疗研究领域的热点.     

髓系抑制性细胞与肿瘤

髓系抑制性细胞(MDSC)是一群髓系来源具有抑制功能的天然免疫细胞,在肿瘤进展中发挥负向免疫调控作用.MDSC具有强大的抑制功能及显著的异质性,通过多种机制调控固有免疫及适应性免疫系统,发挥促肿瘤作用,同时可通过非免疫机制促进肿瘤血管生成及肿瘤转移等.近年来对其分化、增殖、抑制功能等的研究日趋成熟,由此衍生的靶向针对MDSC的肿瘤免疫治疗研究将为肿瘤疫苗的增效及肿瘤的治疗等带来新的希望.     

Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer

It is well established that cancers affect differentiation of dendritic cells and promote systemic expansion of immune suppressive immature myeloid cells. This phenomenon may represent a mechanism of tumor escape from immune attack and could have significant impact on tumor progression. In this review we discuss the role of different tumor-derived factors, which were implicated in abnormal myeloid cell differentiation. The role of reactive oxygen species as well as JAK/STAT signaling in mechanisms of the effects of tumor-derived factors on myeloid cells is also discussed.     

Myeloid-derived suppressor cell role in tumor-related inflammation

Chronic inflammatory state can create a proper environment for neoplastic onset and sustain cancer growth. The inflammatory state that arises at the tumor edge could contribute to immune escape phenomena in many ways. Myeloid-derived suppressor cells (MDSCs), a cell population that contributes to tumor escape, immune tolerance, and suppression, respond to a variety of pro-inflammatory and anti-inflammatory stimuli, which drive their recruitment and activation. Understanding how the inflammatory milieu favours tumor escape through the accumulation of MDSCs could be very useful to improve the efficacy of cancer immunotherapy.     

髓源抑制性细胞与恶性肿瘤的研究进展

髓源抑制性细胞(myeloid derived suppressor cells,MDSCs)是一群异质性细胞,包括多种处于不同分化阶段的髓样细胞,如髓系祖细胞、未成熟的巨噬细胞、粒细胞、单核细胞、树突状细胞等。在荷瘤小鼠的血液、脾脏和肿瘤组织及肿瘤患者的外周血和肿瘤组织中存在大量MDSCs的扩增,与肿瘤的进展密切相关。恶性肿瘤来源的多种因子如粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony stimulating factor,GM-CSF）、白细胞介素（interleukin,IL）-6、S100钙结合蛋白A8/A9（S100 calcium binding protein A8/A9,S100A8/A9）等是导致MDSCs扩增的关键因素。MDSCs可通过抑制机体抗肿瘤免疫、上皮-间质转化(epithelial-mesenchymal transition,EMT）、侵袭、血管生成、转移前小生境形成等多种途径导致肿瘤发生发展。本文主要介绍MDSCs的亚群、功能、募集和活化机制,MDSCs作为预后标志物的价值以及当前靶向MDSCs的抗肿瘤治疗策略,以期加深对MDSCs与恶性肿瘤关系的认识。     

免疫检查点抑制剂治疗相关超进展的研究现状

在多种恶性肿瘤中,免疫检查点抑制剂(ICIs)因临床应用见效显著、治疗应答时间长而成为最有前景的免疫治疗手段之一。与此同时,临床研究发现接受ICIs治疗的患者往往在治疗应答中表现出异质性。越来越多的研究表明,在接受免疫治疗后,部分患者不仅未达到临床获益,反而出现肿瘤进程加速演进,即超进展性疾病(HPD)。HPD已成为患者接受ICIs治疗后进展的新模式。迄今为止,尚未发现可靠的生物学标记物来预测肿瘤在ICIs治疗过程中的加速生长。本文旨在总结目前HPD的定义、相关风险因素、潜在病理生理机制、候选生物学标志物和后续治疗策略。     

Effect of surgical resection of metastatic disease on immune tolerance to cancer. How a systemic disease could be controlled by a local therapy

Surgery represents the only chance of cure for patients with colorectal liver metastases. The results of expanded indications for surgical treatment revealed that even advanced disease can be cured in a significant percentage of cases. What is the explanation for this systemic impact of a local treatment such as surgery? What is different in those patients who can be cured by resection? In this review we analyse the available evidence of the complex relationship between the growing tumour and the immune system. Special attention is directed to the role of T regulatory cells (Tregs) recruited by the tumour to construct a tolerogenic microenvironment in which to grow. Based on the published data we developed the hypothesis that surgery breaks the tumour immune tolerance status because it not only removes the tumour, but also the protective shield of T regulatory cells.     

Myeloid‐derived suppressor cells as effectors of immune suppression in cancer

The tumor microenvironment consists of an immunosuppressive niche created by the complex interactions between cancer cells and surrounding stromal cells. A critical component of this environment are myeloid‐derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells arrested at different stages of differentiation and expanded in response to a variety of tumor factors. MDSCs exert diverse effects in modulating the interactions between immune effector cells and the malignant cells. An increased presence of MDSCs is associated with tumor progression, poorer outcomes, and decreased effectiveness of immunotherapeutic strategies. In this article, we will review our current understanding of the mechanisms that underlie MDSC expansion and their immune‐suppressive function. Finally, we review the preclinical studies and clinical trials that have attempted to target MDSCs, in order to improve responses to cancer therapies.     

肾癌免疫治疗进展

肾癌细胞特殊的生物学特性使大多数肾癌对化疗和放疗不敏感,随着基因技术、肿瘤免疫、分子生物技术的迅速发展,免疫治疗成为较有前景的一种方法。应用免疫细胞、肿瘤疫苗、免疫基因等方法治疗肾癌已取得了很大的进展。现综述肾癌尤其是晚期肾癌在免疫治疗方面的进展。     

Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies

Traditional chemotherapeutics have largely failed to date to produce significant improvements in pancreatic cancer survival. One of the reasons for the resilience of pancreatic cancer towards intensive treatment is that the cancer is capable of high jacking the immune system: during disease progression the immune system is converted from a system that attacks tumor cells into a support structure for the cancer, exerting trophic actions on the cancer cells. This turn-around of immune system action is achieved through mobilization and activation of regulatory T cells, myeloid derived suppressor cells, tumor-associated macrophages and fibroblasts, all of which suppress CD8 T cells and NK cells. This immune suppression occurs both through the expression of tolerance-inducing cell surface molecules, such as PD-L1, as well as through the production of “tolerogenic” cytokines, such as IL-10 and TGF-β. Based on the accumulating insight into the importance of the immune system for the outcome of pancreatic cancer patients multiple new immunotherapeutic approaches against pancreatic cancer are being currently tested in clinical trials. In this review we give an overview of both the immune escaping mechanisms of pancreatic cancer as well as the new immune related therapeutic strategies currently being tested in pancreatic cancer clinical trials.     

抗EGFR-抗CD3双功能抗体介导CIK细胞、LAK细胞或PBLS细胞对胃癌荷瘤裸鼠治疗效果的比较

 目的　比较抗EGFR-抗CD3双功能抗体在体内条件下介导CIK细胞、LAK细胞及人类PBLS细胞三类不同的免疫效应细胞对胃癌细胞的杀伤能力,为临床应用该抗体治疗胃癌的细胞选择提供实验指导。方法　采用化学耦联法合成的抗EGFR-抗CD3双功能抗体分别与CIK细胞、LAK细胞及人类PBLS细胞联合经尾静脉注入SGC7901胃癌细胞移植瘤小鼠体内,同时以等量0.9 % NaCl溶液尾静脉注射建立对照,治疗后检测在体情况下4组对胃癌细胞的杀伤能力,进行组间比较。结果　抗EGFR-抗CD3双功能抗体介导CIK细胞治疗组小鼠肿瘤抑制率为（64.9±7.7）%,显著高于抗EGFR-抗CD3双功能抗体介导LAK细胞及人类PBLS细胞组的（43.5±8.2）%和（39.7±6.5）%（均P＜0.05）,治疗结束时平均肿瘤质量为（473.9±37.7）mg,显著低于其他两组的（764.6±88.3）mg和（829.1±104.4）mg（均P＜0.05）。结论　初步的裸鼠模型治疗实验显示由抗EGFR-抗CD3双功能抗体介导的CIK细胞在体内条件下对胃癌治疗作用优于其他常用的免疫效应细胞。     

Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapy

Immune checkpoint inhibitors-based immunotherapy offers a new effective modality in the treatment of advanced malignancies. Considering the remarkable efficacy of immune checkpoint inhibitors in clinical trials, the FDA has approved a variety of immune checkpoint inhibitors for the treatment of advanced tumors. However, only limited patients with certain cancers can benefit from monotherapy of immune checkpoint inhibitors. Interventional therapy for cancer can not only destroy the primary tumors, but also regulate the immune system through different mechanisms, which provides a potential possibility for the combination of immune checkpoint inhibitors and interventional modalities in cancer treatment. This article reviews the possible synergistic mechanisms of interventional therapy combined with immune checkpoint inhibitors and summarizes the research progress of the combined therapy in cancer treatment.     

非小细胞肺癌T细胞CTLA-4免疫靶向治疗基础与转化性研究现状的思考

细胞毒T淋巴细胞相关抗原4（CTLA-4）是一种白细胞分化抗原,参与免疫反应的负调节。随着非小细胞肺癌（NSCLC）的治疗模式由驱动基因靶向治疗向免疫靶向治疗的转变,CDLA-4已成为一个新的研究热点。本文梳理近年来CTLA-4在NSCLC领域的研究情况,并结合相关基础及临床转化性研究进展作一综述。     

STAT1 inhibits T-cell exhaustion and myeloid derived suppressor cell accumulation to promote antitumor immune responses in head and neck squamous cell carcinoma

Cancers of the oral cavity remain the sixth most diagnosed cancer worldwide, with high rates of recurrence and mortality. We determined the role of STAT1 during oral carcinogenesis using two orthotopic models in mice genetically deficient for Stat1. Metastatic (LY2) and nonmetastatic (B4B8) head and neck squamous cell carcinoma (HNSCC) cell lines were injected into the oral cavity of Stat1 deficient (Stat1^−/−) and Stat1 competent (Stat1^+/+) mice. Stat1^−/− mice displayed increased tumor growth and metastasis compared to Stat1^+/+ mice. Mechanistically, Stat1^−/− mice displayed impaired CD4+ and CD8+ T-cell expansion compared to Stat1^+/+ mice. This was associated with enhanced T-cell exhaustion, and severely attenuated T-cell antitumor effector responses including reduced expression of IFN-γ and perforin at the tumor site. Interestingly, tumor necrosis factor (TNF)-α production by T cells in tumor-bearing mice was suppressed by Stat1 deficiency. This deficiency in T-cell expansion and functional responses in mice was linked to PD-1 and CD69 overexpression in T cells of Stat1^−/− mice. In contrast, we observed increased accumulation of CD11b+ Ly6G+ myeloid derived suppressor cells in tumors, draining lymph nodes, spleens and bone marrow of tumor-bearing Stat1^−/− mice, resulting in a protumorigenic microenvironment. Our data demonstrates that STAT1 is an essential mediator of the antitumor response through inhibition of myeloid derived suppressor cell accumulation and promotion of T-cell mediated immune responses in murine head and neck squamous cell carcinoma. Selective induction of STAT1 phosphorylation in HNSCC patients could potentially improve oral tumor outcomes and response to therapy.     

Review and prospect of immune checkpoint blockade therapy represented by PD-1/PD-L1 in the treatment of clear cell renal cell carcinoma

As a common tumor of the urinary system, the morbidity and mortality related to renal carcinoma, are increasing annually. Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell carcinoma, accounting for approximately 75% of the total number of patients with renal cell carcinoma. Currently, the clinical treatment of ccRCC involves targeted therapy, immunotherapy, and a combination of the two. In immunotherapy, PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment. However, as treatment progresses, some patients gradually develop resistance to immunotherapy. Meanwhile, other patients experience great side effects after immunotherapy, resulting in a survival status far lower than the expected survival rate. Based on these clinical problems, many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results. We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.