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.     

脂肪酸代谢影响肿瘤免疫微环境与免疫治疗的研究进展

肿瘤免疫微环境是肿瘤细胞周围的微小结构,对肿瘤的发生、发展起着重要作用,也是多种免疫治疗靶向的核心区域, 其调控因素非常复杂。肿瘤免疫微环境中存在促进免疫耐受和肿瘤免疫逃逸的多种调控机制,除免疫检查点分子上调、抗原提 呈丢失等过程外,还包括免疫细胞的代谢重编程。免疫细胞的脂肪酸代谢是肿瘤免疫微环境的关键代谢过程,受肿瘤细胞的信 号调控和营养争夺影响可发生重编程,其在肿瘤免疫治疗中的调控规律是目前新兴的研究热点。本文集中回顾了脂肪酸代谢对 肿瘤免疫微环境中效应T细胞、记忆T细胞、调节性T细胞、肿瘤相关巨噬细胞等免疫细胞生存和功能的调节机制,讨论了近年来 免疫细胞脂肪酸代谢重编程影响免疫检查点阻断治疗、过继细胞治疗、肿瘤治疗性疫苗等免疫治疗效果的最新进展,总结了新近 出现的免疫相关的脂肪酸代谢调控靶点和相关药物,指出肿瘤相关免疫细胞脂肪酸代谢的独有特点和研究难点,为肿瘤免疫治 疗提供新的思路和见解。     

肠道菌群对肿瘤微环境调节的研究进展

摘 要：肿瘤微环境是肿瘤生长所处的环境,作为肿瘤细胞赖以生存的场所,对肿瘤的演变起着至关重要的作用,肿瘤微环境能调控肿瘤的生长,促进肿瘤侵袭和转移,介导肿瘤的免疫逃避,对肿瘤的发展起着关键性作用。因此,研究肿瘤微环境的调节机制对肿瘤的治疗具有积极意义。肠道菌群与肿瘤的发生发展具有相关性,肠道菌群能够调节肿瘤微环境,促进肿瘤发展。全文综述肿瘤微环境在肿瘤发展中的作用和介导肿瘤免疫逃避的细胞机制和分子机制,简述肠道菌群通过对肿瘤炎性微环境和免疫微环境的调节来影响肿瘤的发展,从而为肿瘤的治疗尤其是免疫治疗开发基于肠道菌群为靶点的新方法提供思路。     

IFN-γ在肿瘤免疫及免疫治疗中的作用

IFN-γ在抗肿瘤过程中发挥了重要作用,近年来人们逐渐认识到了其在肿瘤免疫治疗中的必要性。IFN-γ作用于肿瘤发生发展的全过程,其在抗肿瘤方面的作用机制主要分为免疫机制和非免疫机制。IFN-γ可以直接抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、抑制肿瘤血管生成,协同固有免疫和适应性免疫的NK、NKT细胞、γδT细胞以及CD4 + /CD8 + T细胞等完成肿瘤杀伤。然而也有报道IFN-γ的促肿瘤作用,主要表现为在长期慢性炎症和肿瘤微环境中重塑免疫微环境促进免疫逃逸。因此,在肿瘤免疫治疗中要注意IFN-γ的双向效应,防止产生定向选择造成肿瘤免疫抑制。     

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。     

肿瘤血管新生在肿瘤免疫治疗中的研究进展

肿瘤血管新生,与肿瘤的发生和发展密切相关,同时在肿瘤的免疫治疗中也有着不可忽视的作用。肿瘤血管异常可造成间质压升高、缺氧、酸性等微环境的改变,进而导致促进肿瘤免疫的细胞减少,而抑制肿瘤免疫的细胞相应增多;此外,肿瘤微环境（tumor microenvironment,TME）中的免疫细胞也在肿瘤血管新生和血管内皮细胞重构方面起到重要作用。本文将对肿瘤血管生成机制、血管新生与肿瘤免疫之间的关系以及血管新生对肿瘤免疫治疗的影响进行简要综述。     

基于肿瘤免疫微环境联合免疫治疗卵巢癌的研究进展

卵巢癌在女性生殖道恶性肿瘤中致死率最高,既往的标准治疗是手术加化疗,近几年以聚腺苷二磷酸核 糖聚合酶抑制剂为主的靶向治疗延长了部分患者的生存期,但仍然会面临耐药及复发。近年免疫治疗发展迅速,然 而已有的临床研究表明单一的免疫治疗在卵巢癌中疗效有限。肿瘤免疫微环境中免疫抑制性网络,在卵巢癌的发 生发展中起着重要作用,深入探索其机制有助于制定卵巢癌免疫治疗策略。本文综述了肿瘤免疫微环境与卵巢癌 的相互作用,针对免疫微环境,免疫治疗联合化疗和靶向治疗,以及过继细胞治疗等治疗方式的研究进展,为卵巢癌 得到长期持久的个性化治疗提供理论依据。     

乳腺肿瘤免疫微环境及其在临床免疫治疗中的应用

免疫微环境中存在不同激活状态的免疫细胞。不同分子表型的乳腺肿瘤中免疫细胞浸润程度不同,其免疫细胞的数量和状态可作为预测乳腺肿瘤患者预后和疗效的重要指标。因此,研究免疫细胞之间及其与肿瘤细胞之间的相互作用机制以及免疫细胞作为诊断标志物和治疗靶点的临床应用价值,是当今肿瘤领域的热点。笔者总结了肿瘤免疫微环境在乳腺肿瘤发生、发展中的作用及其作为免疫治疗靶点的临床应用潜能。     

肿瘤微环境与免疫治疗耐药的关系及应对

免疫治疗的革命性进展开创了肿瘤精准化治疗的新时代,为肿瘤患者带来了长期生存获益。然而,在临床实践中仍存在免疫治疗耐药等诸多挑战。肿瘤微环境（tumor microenvironment,TME）的动态抑制性变化、异质性等特点在肿瘤发生发展、恶性进展、免疫逃逸和治疗耐药中发挥重要作用。因此,了解免疫治疗与TME之间的相互作用不仅对剖析其作用机制至关重要,而且有助于为提高免疫治疗疗效提供新的途径。本综述就TME的起源、动态抑制性变化、异质性特点进行总结,介绍关于TME如何影响免疫疗效的研究进展,以期通过靶向TME角度或联合治疗方式寻求优化免疫治疗疗效的应对策略。     

血液系统恶性肿瘤细胞焦亡调控肿瘤免疫微环境分子机制的研究进展

细胞焦亡与免疫微环境和疾病的关系越来越受关注。细胞焦亡在抗肿瘤免疫治疗中发挥双重效应, 一方面促进炎性因子的释放, 形成肿瘤微环境, 抑制肿瘤免疫, 另一方面诱发肿瘤炎症反应, 抑制肿瘤细胞的增殖。细胞焦亡、免疫微环境和肿瘤的关系在不同的组织和遗传背景是不同的。现就细胞焦亡的分子机制、肿瘤免疫微环境在血液系统恶性肿瘤中的调控作用进行综述, 以期为基于细胞焦亡调控免疫微环境为靶点的抗血液系统恶性肿瘤治疗与研究提供思路。     

卵巢癌肿瘤微环境的三维细胞培养模型研究进展

卵巢癌(Ovarian cancer,OC)是一种具有侵袭性和致命性的癌症。越来越多的研究表明,肿瘤微环境(Tumor microenvironment,TME)通过各种机制参与促进卵巢癌发生、发展、免疫抑制和炎性反应。TME包括肿瘤血管和淋巴管,以及肿瘤细胞、间质细胞、免疫细胞和细胞外基质(ECM)等。本文结合近年来的文献报道,综述了目前常用的卵巢癌TME三维细胞培养模型,以及总结了许多不包含原始基质细胞的三维模型,旨在总结和寻找卵巢癌治疗的新途径和新方法。     

卵巢癌对富脂大网膜的器官趋向性转移的研究进展

肿瘤转移是一个复杂的多步骤过程,涉及到肿瘤细胞与肿瘤微环境中多种基质成分之间的相互作用.卵巢癌是最致命的妇科恶性肿瘤,以腹膜播散性转移为特征.有证据表明卵巢癌对富含脂肪的大网膜具有特异的转移倾向,大网膜在这个过程中起关键作用,其在腹腔内形成转移性肿瘤微环境促进卵巢癌转移.考虑到卵巢癌转移的独特生物学特性,在富含脂肪的转...     

Cancer related inflammation: the macrophage connection

Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. In the tumor microenvironment neoplastic cells shape the differentiation and functional orientation of TAM which, in turn, express several protumoral functions, including secretion of growth factors and matrix-proteases, promotion of angiogenesis and suppression of adaptive immunity. This review analyzes our current knowledge of TAM and their involvement in tumor development and progression. The interplay between TAM and neoplastic cells represents a promising target of future therapeutic approaches.     

Pattern response of dendritic cells in the tumor microenvironment and breast cancer

Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development, including malignancy grade and patient prognosis, is influenced by various mutations that occur in the tumor cell and by the immune system’s status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Among the immune response cells, dendritic cells (DCs) play a key role in the induction and maintenance of anti-tumor responses owing to their unique abilities for antigen cross-presentation and promotion of the activation of specific lymphocytes that target neoplasic cells. However, the tumor microenvironment can polarize DCs, transforming them into immunosuppressive regulatory DCs, a tolerogenic phenotype which limits the activity of effector T cells and supports tumor growth and progression. Various factors and signaling pathways have been implicated in the immunosuppressive functioning of DCs in cancer, and researchers are working on resolving processes that can circumvent tumor escape and developing viable therapeutic interventions to prevent or reverse the expression of immunosuppressive DCs in the tumor microenvironment. A better understanding of the pattern of DC response in patients with BC is fundamental to the development of specific therapeutic approaches to enable DCs to function properly. Various studies examining DCs immunotherapy have demonstrated its great potential for inducing immune responses to specific antigens and thereby reversing immunosuppression and related to clinical response in patients with BC. DC-based immunotherapy research has led to immense scientific advances, both in our understanding of the anti-tumor immune response and for the treatment of these patients.     

The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment

Despite recent progresses in tumor therapy and increased knowledge in tumor biology, tumor remains a common and lethal disease worldwide. Cancer stem cells (CSCs) are a subset of cancer cells with a stem cell-like ability, which may drive tumor growth and recurrence and are resistant to many current anticancer treatments. Solid tumors are regarded as “organs” which are comprised of cancer cells and the tumor stroma. The tumor microenvironment makes up the stroma of the tumor, which occupies the majority of the tumor mass, including the extracellular matrix (ECM), mesenchymal stem cells (MSCs), endothelial cells, immune cells, and, what is more, networks of cytokines and growth factors. The microenvironment or niche surrounding CSCs largely governs their cellular fate. Recent work has revealed that the microenvironment supports CSC self-renewal and simultaneously serves as a physical barrier to drug delivery. The tumor microenvironment plays pivotal roles in each stage of tumor development. Knowledge about the interactions of CSCs with their microenvironment would seem to be of most importance for developing new treatment strategies.     

肿瘤微环境中肿瘤相关巨噬细胞与上皮间质化“对话”的研究进展

肿瘤微环境决定了许多癌症的发生和发展。肿瘤相关巨噬细胞是肿瘤微环境中协调炎症和癌症之间的关键因子。上皮间质化的激活通常需要肿瘤细胞与局部肿瘤微环境组分（包括肿瘤相关巨噬细胞）之间的“对话”。在本篇综述中,临床和实验证据证明肿瘤相关巨噬细胞促进肿瘤侵袭和转移以及它在肿瘤转移级联反应中与上皮间质化的相互作用。此外,本文总结了以介入肿瘤相关巨噬细胞和上皮间质化的肿瘤细胞“对话”的信号通路作为肿瘤转移治疗的潜在靶点的治疗策略。     

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 in hepatocellular carcinoma (review)

The tumor microenvironment has been largely studied as a dynamic system orchestrated by inflammatory cells, including cancer cells, stroma as well as the extracellular matrix. It is useful to describe and predict the phenotypic characteristics of cancer. Furthermore, a better understanding of its interplay with the various aspects of the tumor cells may be utilized for the discovery of novel molecular targets. Liver cancer is considered a model of the relation occurring between the tumor micro-environment and tumor development. The chronic inflammatory status of the liver, sustained by the infection of hepatitis viruses, as well as the production of cytokines and growth factors within the parenchyma, lead to an intricate microenvironment. The identification of novel molecular therapeutic targets may improve the outcome of patients with liver cancer as it remains the third leading cause of cancer death worldwide. In the present study, the tumor microenvironment in hepatocellular carcinoma (HCC) was explored by a review of the literature. Studies on hepatitis virus infections and the consequent chronic inflammatory status were examined. In this context, immune-mediated and/or virus-related molecular mechanisms have been hypothesized as being responsible for liver cancer development. The interlink among HCC microenvironment components, comprising cellular elements, cytokines, growth factors and several proteins is also described together with the role of matrix metalloproteinases in HCC development. Finally, the rationale for targeting tumor-stromal interface is summarized in the context of new therapeutic opportunities.     

Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype.

Traditionally, prostate cancer treatment, as well as all cancer treatment, has been designed to target the tumor cell directly via various hormonal and chemotherapeutic agents. Recently, the realization that cancer cells exist in complex microenvironments that are essential for the tumorigenic and metastatic potential of the cancer cells is starting the redefine the paradigm for cancer therapy. The propensity of prostate cancer cells to metastasize to bone is leading to the design of novel therapies targeting both the cancer cell as well as the bone microenvironment. Tumor cells in the bone interact with the extracellular matrix, stromal cells, osteoblasts, osteoclasts, and endothelial cells to promote tumor-cell survival and proliferation leading to a lethal phenotype that includes increased morbidity and mortality for patients with advanced prostate cancer. Several strategies are being developed that target these complex tumor cell-microenvironment interactions and target the signal transduction pathways of other cells important to the development of metastases, including the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment. Current and new therapies in metastatic prostate cancer will comprise a multitargeted approach aimed at both the tumor cell and the tumor microenvironment. Here, we review the current therapeutic strategies for targeting the prostate cancer-bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development.     

Collagen as a double-edged sword in tumor progression

It has been recognized that cancer is not merely a disease of tumor cells, but a disease of imbalance, in which stromal cells and tumor microenvironment play crucial roles. Extracellular matrix (ECM) as the most abundant component in tumor microenvironment can regulate tumor cell behaviors and tissue tension homeostasis. Collagen constitutes the scaffold of tumor microenvironment and affects tumor microenvironment such that it regulates ECM remodeling by collagen degradation and re-deposition, and promotes tumor infiltration, angiogenesis, invasion and migration. While collagen was traditionally regarded as a passive barrier to resist tumor cells, it is now evident that collagen is also actively involved in promoting tumor progression. Collagen changes in tumor microenvironment release biomechanical signals, which are sensed by both tumor cells and stromal cells, trigger a cascade of biological events. In this work, we discuss how collagen can be a double-edged sword in tumor progression, both inhibiting and promoting tumor progression at different stages of cancer development.