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。     

铁代谢及相关蛋白的miRNA在肿瘤中的研究进展

铁是促进细胞增殖和生长的必需营养物质,涉及许多代谢过程,肿瘤细胞比正常的非恶性细胞有更高的铁需求。由于铁进行氧化还原循环并参与自由基产生,机体多余的铁会增加癌症的风险。铁代谢紊乱与肿瘤的发生和发展有关。参与铁代谢的相关蛋白在肿瘤的发生发展中起重要作用。miRNA与肿瘤关系是近年来研究的热点,铁代谢相关蛋白miRNA在肿瘤发生发展中起到重要作用,这些可能为肿瘤的诊断以及治疗提供新的思路。     

中性粒细胞在肿瘤发生发展及免疫治疗中的作用

中性粒细胞作为机体的重要免疫细胞,在感染、自身免疫性疾病等多种炎症反应中发挥重要作用。然而,中性粒细胞在肿瘤的发生发展过程中也扮演重要角色。一方面,中性粒细胞能够通过杀伤肿瘤细胞发挥抗肿瘤作用;另一方面,中性粒细胞也可以通过分泌多种细胞因子或与其他类型细胞相互作用来促进肿瘤细胞发生免疫逃逸。由于中性粒细胞能够通过多种机制来促进肿瘤的发生发展,因此靶向中性粒细胞的免疫治疗也成为了肿瘤免疫治疗的一个新的思路。本文通过介绍中性粒细胞在肿瘤演进过程中发挥的抗肿瘤效应,促进肿瘤免疫逃逸以及中性粒细胞相关的免疫治疗等方面来阐述中性粒细胞在肿瘤发生发展以及免疫治疗中的重要性。     

中性粒细胞与肿瘤复杂相关性的研究进展

中性粒细胞具有多重功能,包括分泌趋化因子和细胞因子的能力,形成细胞外陷阱以及对肿瘤增殖与转移进行调控的能力。有关其可塑性与异质性的研究表明,循环中性粒细胞与肿瘤相关中性粒细胞在肿瘤增殖与转移调控中的作用十分显著,并表现为双重作用。一方面,中性粒细胞能够促进肿瘤炎症、肿瘤细胞增殖与侵袭以及肿瘤血管的生成,并且能够通过抑制T细胞的活性,促进肿瘤免疫逃避。另一方面,中性粒细胞能够促进T细胞抗肿瘤效应,并且可以通过产生相应的细胞因子参与肿瘤抑制。此前,肿瘤相关中性粒细胞的研究多以动物模型为依据,近年来,有研究进一步指出了对人类肿瘤相关中性粒细胞的认识,并探讨了中性粒细胞成为肿瘤免疫治疗新靶点的可能性。目前,对于肿瘤与中性粒细胞复杂相关性的多项研究表明,细胞治疗对肿瘤生物学的认识、肿瘤标志物的开发以及肿瘤的治疗均具有重要作用。本文就中性粒细胞与肿瘤复杂相关性研究的进展作一综述。     

热疗对肿瘤免疫微环境中免疫细胞及免疫相关细胞因子的影响

随着对肿瘤热疗和肿瘤免疫微环境(TIME)的深入研究,近年来热疗对TIME的作用越来越受到学者们的重视。本文就目前国内外研究进展,对热疗与TIME中几类主要免疫细胞和免疫相关细胞因子的影响及作用机制作一综述。全面而透彻的了解热疗对TIME的调控作用,有助于为肿瘤治疗提供新的思路和方法。     

肿瘤相关中性粒细胞与肿瘤的发生和发展

肿瘤微环境中除了肿瘤细胞外,还存在多种类型的其他细胞,包括基质细胞、内皮细胞和各种免疫细胞（如CD4+和CD8+T细胞、树突状细胞、NK细胞、巨噬细胞、中性粒细胞等）。近年来研究发现,肿瘤相关中性粒细胞（tumor-associated neutrophils, TANs）在肿瘤发生和发展中发挥着重要的作用。TANs可以通过多种机制促进肿瘤的生长和转移,这些机制包括TANs释放的弹性蛋白酶促进肿瘤增殖和转移,TANs分泌基质金属蛋白酶促进肿瘤血管的生成,同时高度活化的TANs也可杀伤肿瘤细胞起抗肿瘤的作用。对TANs的深入研究为肿瘤免疫提供了新的认识,以TANs及其分泌的一些分子作为靶点来调控TANs的功能,可能成为干预肿瘤发生、发展的重要方法。     

铁死亡在泌尿系统肿瘤中的作用及其机制研究进展

铁死亡是近年来新发现的一种不同于凋亡、坏死和自噬的程序性细胞死亡。细胞内谷胱甘肽及谷胱甘肽过氧化物酶抗氧化防御系统调控异常及铁离子依赖性膜结构脂质过氧化的蓄积是铁死亡发生的主要病理生理改变。铁死亡参与包括肿瘤、缺血再灌注损伤及神经系统疾病等多种疾病的发生发展过程。近年来研究发现铁死亡与泌尿系统肿瘤密切相关,本文概述了铁死亡在泌尿系统肿瘤发生及进展中作用的相关调控分子机制,旨在为泌尿系统肿瘤的临床治疗提供新的方向。     

肿瘤低氧微环境对免疫应答的调控及其与肿瘤的关系

低氧是造血、炎症、免疫应答耐受、组织损伤和肿瘤等过程中普遍存在的一种生理或病理现象。组织中的低氧微环境一方面能招募免疫细胞迁移到低氧组织,另一方面诱导其代谢方式切换为低氧代谢,同时改变其免疫功能。并且,肿瘤组织的低氧状态对天然免疫和适应性免疫具有不同的调控作用。本文着重对哺乳动物细胞的低氧适应机制、低氧对天然免疫和适应性免疫细胞的分化发育、功能调控及其在肿瘤发生发展过程中的作用进行综述,研究和认识肿瘤组织低氧微环境对免疫系统的功能调控也会为肿瘤治疗提供新的策略。     

肿瘤脂代谢重编程及其对肿瘤和免疫的影响

肿瘤细胞脂代谢在肿瘤发生过程中进行了重编程,与肿瘤发生发展、侵袭和转移等密切相关,是肿瘤演进过程中出现的一个普遍而又至关重要的代谢特征。同时,肿瘤微环境中免疫细胞亦发生了异常脂代谢,且肿瘤脂代谢重编程对免疫微环境中细胞的功能和状态也产生影响,进一步促进其恶性生物学行为。目前,通过对肿瘤异常脂代谢及其对肿瘤免疫的影响的广泛探究,在发现肿瘤代谢特征和其影响肿瘤生物学行为的分子机制,以及肿瘤演进过程中代谢的适应性和复杂性等方面取得了众多的新突破。靶向肿瘤和免疫脂代谢相关基因与酶的研究已为肿瘤防治提供了有力的证据、开辟了新的思路,并为抗肿瘤治疗策略带来变革,有望在直接靶向肿瘤的同时靶向免疫细胞脂代谢以激活抗肿瘤免疫反应,实现“双管齐下”的治疗模式。本文综述了肿瘤细胞和免疫细胞的不同脂代谢特征以及不同脂质代谢对肿瘤演进和免疫细胞功能的重要影响,并概述了针对肿瘤免疫脂代谢异常的抗肿瘤治疗策略。     

乳酸脱氢酶与肿瘤免疫代谢研究进展

不同免疫细胞亚群的代谢特征有所不同,抗肿瘤免疫细胞主要以有氧酵解和谷氨酰胺分解代谢提供代谢的物质与能量,而促进肿瘤发生和进展的抑制性免疫细胞亚群可利用肿瘤细胞代谢产物通过脂肪酸代谢等途径获取能量及中间产物。乳酸作为糖酵解途径的重要产物,直接或间接地影响肿瘤生物学行为,参与肿瘤免疫微环境调控。乳酸代谢的关键酶乳酸脱氢酶（LDH）常在肿瘤组织中高表达,是肿瘤微环境中连接各种免疫细胞代谢的关键酶之一,可激活某些信号传导途径和调控免疫应答参与肿瘤发生、发展。LDH水平升高主要由于肿瘤糖酵解活性增加和肿瘤缺氧坏死引起,其为免疫抑制性微环境的重要驱动者,LDH水平在一定程度上反映并可用于肿瘤糖酵解活性和免疫代谢状态的评估。本文对LDH与T淋巴细胞、巨噬细胞、树突状细胞等免疫细胞的代谢相关研究进行综述,旨在探究其在恶性肿瘤预后评估、抗肿瘤治疗尤其是免疫治疗疗效预测及监测中的可能应用。     

Circadian-rhythm of tumor growth in non-vascularized tumor

Circadian-Rhythms of tumor growth rates of Walker-256 implanted in the dorsum side of hind paw of Wistar rats (Male 5-6 weeks age) were observed. Tumor size was measured at 7 A.M. and 7 P.M. The tumor growth rate was determined by the following method. Rday = T (P.M.)/T (A.M.). Rnight = T (A.M.)/T (previous P.M.). Rday and Rnight: Tumor growth rate during day and night, respectively. T: Tumor size. The tumor growth rate, for those less than 750 mm3 in size and in which tumor vessels did not form yet, was 0.10 +/- 0.5 on Rday, 0.29 +/- 0.12 on Rnight (p less than 0.05). Tumors of more than 1,500 mm3 forming tumor vessels did not show a significant difference in the degree of the tumor growth rate (Rday: 0.14 +/- 0.07; Rnight: 0.212 +/- 0.05) (p greater than 0.05). Tumors in which vessels were injured and showed microvascular disturbance due to MMC (A. i) or thermochemotherapy using warmed physiological saline injected into tumor vessels after chemotherapy, were damaged on Rday and enhanced on Rnight for 3-7 days after these kinds of treatment. The tumor in unformed tumor vessels or damaged types showed, rapid size increase at night. Therefore, the Circadian-Rhythm tumor vessels in microtumor or damaged tumor may be treated with antimetabolic agents such as 5-FU at night for inhibition of microtumor or micrometastatic tumor.     

肿瘤抗原在肿瘤研究中的应用

近年来随着肿瘤抗原筛选鉴定方法的多样化,已鉴定出了大量的肿瘤抗原,抗原的分类越来越全面,肿瘤抗原的基础性研究已经深入到其他学科,肿瘤抗原的检测诊断则在临床上应用越来越广泛,而针对不同抗原的免疫治疗也更加具体可行.     

肿瘤微环境中的炎性机制与肿瘤转移

炎性微环境是肿瘤微环境中影响肿瘤复发转移的关键因素之一.肿瘤炎性微环境可以通过调节上皮细胞向间充质细胞转变,启动肿瘤转移;可以通过降解细胞外基质从而破坏细胞外基质膜促进肿瘤细胞的侵袭;同时,炎性微环境促进肿瘤血管的新生为肿瘤的发生发展提供保障.     

Detection of circulating tumor cells and of tumor DNA in plasma during tumor progression in rats

The role and clinical significance of circulating tumor cells and of tumor DNA in the plasma have not yet been clarified. In the present study, we compared rates of detection of tumor-derived DNA in the buffy coat to those in plasma from tumor-bearing rats, and we attempted to correlate these rates with the progression of tumors. We injected DHD/K12-PROb cancer cells subcutaneously into BD-IX rats and divided the animals into six groups according to the time between the injection of tumor cells and euthanasia. After euthanasia, macroscopic metastases were assessed and samples of blood and lung were collected. We used mutant allele-specific amplification by PCR to detect tumor-derived DNA. We detected tumor DNA in lung samples from the first week after inoculation, in plasma from the third week and in the buffy coat from the fifth week. All animals analyzed on the 11th week had macro- or micrometastases in their lungs. Regardless of group, the rate of PCR-positive plasma samples was significantly higher than that of circulating tumor cells (P=0.005). In animals with metastases, this difference was also statistically significant (P=0.008). However, neither the detection of tumor DNA in the plasma nor the presence of circulating tumor cells was strongly correlated with the presence of metastases. Thus, cell-free tumor DNA was detected sooner and more frequently than circulating tumor cells and the dissemination of tumor DNA in the plasma seems to be much more common than detectable hematogenic tumor cells during the spread of colorectal cancer.     

肿瘤免疫抑制微环境对肿瘤免疫治疗作用的研究进展

肿瘤免疫抑制微环境是肿瘤微环境中起抑制免疫功能的部分。其组成包括抑制性细胞和抑制性细胞因子。近年来,因其在肿瘤免疫中的重要作用,CAR－T和PD－1／PD－L1信号通路已成为免疫治疗的研究热点,它们可通过不同的机制产生免疫抑制作用,从而促进肿瘤进展。因此,针对以上机制采取更有效的抗肿瘤疗法有可能减缓肿瘤进展。本文现就免疫抑制微环境对CAR－T疗法和PD－1／PD－L1信号通路在抗肿瘤过程中的作用进行综述。     

Modulation of tumor induced angiogenesis in Ehrlich ascites tumor

In this study the enzyme glutaminase, purified from the ascites fluid of ovarian cancer patients, was analysed for its antiangiogenic activity. Intraperitoneal administration of this enzyme reduces the number of tumor directed capillaries in solid and ascites tumor bearing Swiss mice induced by transplantation of Ehrlich ascites cells. The enzyme has a critical role in regulating the secretion of vascular endothelial growth factor (VEGF) from tumor cell and in turn tumor growth. Glutamine analogue like 6-diazo, 5- oxo L-norleucine (DON) is also found to be effective in regulating vascular endothelial growth factor (VEGF) secretion from tumor cells in vitro. Treatment with enzyme reduced serum VEGF levels of the tumor induced animals. In vitro VEGF production by EAC cells was reduced in a concentration dependent manner in presence of glutamine analogue.     

肿瘤相关巨噬细胞与肿瘤关系的研究进展

肿瘤相关巨噬细胞（ Tumor associate macrophages ,TAMs）是肿瘤的炎症微环境与肿瘤细胞间的重要信使。它是从血液中的单核细胞演变而来,主要通过集落刺激因子（ Colony -stimulating factor , CSF）趋化至肿瘤组织中。本文简述了TAMs通过影响血管生成和淋巴管生成,抑制免疫,调节基质,与干细胞相互作用等方面促进肿瘤的进展。分析表明靶向于TAMs的治疗策略是未来治疗肿瘤的一个新方向。     

Role of tumor proteinases in tumor cell-induced platelet aggregation

In a previous work we found a correlation between in vivo metastatic potential of cancer cells and their platelet aggregating activity in sublines of the mFS6 murine fibrosarcoma. In the present study the effects of different proteinase inhibitors on platelet aggregation induced by these cells were investigated. When the platelets were incubated with the inhibitors, only those effective against cysteine proteinases strongly reduced platelet aggregation by cancer cells; serine protease inhibitors, including hirudin, had no effect on platelet response. Incubation of neoplastic cells with the same inhibitors gave similar, though less evident results. Addition of neoplastic cells to platelet-rich plasma also caused significant production of fibrinopeptide A, more by the less malignant cells. Thus, in this experimental model a cysteine proteinase of the neoplastic cells appears to play an important role in the platelet aggregation induced by them, and this property was detected in the M4 cells with high metastatic in vivo activity.     

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.