代谢重编程介导肿瘤微环境免疫抑制的研究评述

近十年免疫疗法在肿瘤的治疗中取得了突破性进展,导致肿瘤治疗的范式转变。然而大多数患者并不能从中获益,如何提高患者免疫治疗的应答率是亟待解决的热点问题。免疫疗法的成功有赖于机体免疫效应细胞的活化及杀伤效应。然而,在肿瘤微环境严苛的代谢和营养应激下,免疫细胞的功能常处于紊乱状态,导致抗肿瘤免疫应答受损。因此,通过靶向肿瘤代谢重塑免疫微环境,恢复抗肿瘤免疫应答,有望在与免疫疗法的联合应用中取得协同效应。本文着重探讨代谢重编程及其代谢产物如何调节抗肿瘤免疫应答,旨在为肿瘤免疫治疗提供新的思路和方法。     

代谢重编程介导肿瘤免疫微环境重塑的现状和展望

代谢重编程是肿瘤的特征之一,也是肿瘤治疗的重要潜在靶点。肿瘤和免疫细胞之间的相互作用对代谢重编程的影响是决定抗肿瘤免疫应答的关键因素之一。肿瘤代谢不仅在肿瘤发生和维持肿瘤细胞生存中发挥了关键作用,并且可以通过释放代谢产物,如乳酸、PGE2等来影响免疫细胞进而影响肿瘤免疫微环境。这种肿瘤细胞与免疫细胞之间的相互作用导致了肿瘤免疫微环境中的代谢竞争,限制了营养物质的正常代谢,形成酸性环境,最终导致抗肿瘤免疫反应减弱和免疫抑制性微环境的形成。此外,免疫细胞发生免疫应答的过程中存在代谢方式的改变,即在增殖、分化和执行细胞功能的过程中会发生代谢重编程。因此,了解肿瘤免疫微环境中肿瘤细胞和免疫细胞的代谢重编程的调节机制,可以使研究人员在抗肿瘤免疫治疗中获得靶向代谢途径的治疗思路。     

肿瘤微环境内代谢变化与肿瘤免疫治疗研究

肿瘤免疫疗法在肿瘤治疗领域取得重大进展.许多临床试验已经揭示了基于激活肿瘤特异性T细胞的免疫检查点抑制剂在肿瘤治疗方面的显著疗效.然而,只有部分癌症患者可以从免疫疗法中受益,越来越多的证据表明,可能是由于免疫抑制性肿瘤微环境(tumor mi-croenvironment,TME)的代谢重编程不足,使得抗肿瘤免疫力的恢...     

肿瘤微环境下的代谢重编程调控

肿瘤的发生、增殖和转移与其微环境密切相关。肿瘤细胞通常被不同类型的细胞层层包围和设防,这些细胞包括成纤维细胞、免疫细胞及神经纤维和细胞外基质,其对肿瘤细胞设下防线使得肿瘤细胞处于低氧或者营养匮乏状态,迫使肿瘤细胞通过调控自身代谢来从周围环境中摄取充足的营养物质以此抵御免疫细胞的杀伤。本文从两个方面来阐述肿瘤细胞的代谢重编程的调控作用,一方面在营养压力条件下,肿瘤细胞以特殊的方式获取和利用各种营养物质来支持其迅速和无限制的增殖,其中除了传统的营养物质,还包括乳酸、酮体、乙酸、支链氨基酸等非传统的代谢原料,这些物质在肿瘤的发展过程中也起着至关重要的作用;另一方面氧气和营养的匮乏使得肿瘤细胞通过代谢的改变影响和调控周围免疫细胞及成纤维细胞,肿瘤组织的细胞基质成分肿瘤相关成纤维细胞能够提供多种营养物质或生长因子来调控肿瘤细胞的代谢,而肿瘤细胞的多种代谢产物能够影响周围免疫细胞的正常功能,抑制其抗肿瘤作用,最终使得微环境向有利于肿瘤细胞增殖和发展的方向进行转变。     

肿瘤微环境中T淋巴细胞代谢重编程的研究进展

先天性免疫系统和适应性免疫系统通过各种机制发挥抗肿瘤作用,推动了肿瘤免疫疗法的空前发展。研究表明,肿瘤微环境中的免疫细胞在增殖、分化和执行效应功能的过程中发生代谢重编程,与抗肿瘤免疫反应密切相关。众所周知,T淋巴细胞是最主要的抗肿瘤免疫细胞类型。全文主要讨论不同T淋巴细胞亚群代谢重编程途径对抗肿瘤免疫反应的影响,以及靶向效应T细胞代谢的抗肿瘤治疗策略。     

肿瘤相关成纤维细胞的代谢重编程与肿瘤进展的关系

肿瘤的生长并不完全由肿瘤细胞本身决定,肿瘤相关成纤维细胞(CAF)是肿瘤微环境的主要组成部分,在肿瘤的代谢、生长、转移、免疫逃逸和化疗耐药等方面具有重要作用。CAF的代谢重编程使其更倾向于有氧糖酵解,被称为"温伯格效应"。目前认为,CAF的代谢重编程调控机制可能与致癌基因c-myc、缺氧诱导因子1α和腺苷一磷酸(AMP)活化的蛋白激酶有关。代谢重编程的CAF可通过多种途径促进肿瘤的生长、发展:肿瘤微环境中的CAF可以通过分泌大量的细胞因子、趋化因子和促血管生成因子间接或直接调节肿瘤免疫;通过调节肿瘤间质液压、酸化肿瘤微环境,以及分泌可溶性因子促进肿瘤耐药;肿瘤组织中的CAF可募集抑制性免疫细胞,在肿瘤局部形成抑制性免疫微环境,促进上皮-间充质转化,激活肿瘤细胞增殖的信号通路从而促进肿瘤生长、耐药,形成恶性循环。阻断肿瘤、CAF和免疫微环境间的相互作用,可能成为未来肿瘤治疗的靶点。     

肿瘤微环境与乳腺癌细胞糖代谢重编程研究进展

摘 要：乳腺癌的进展、转移能力除了取决于肿瘤细胞的特性之外,还取决于肿瘤微环境对肿瘤细胞葡萄糖代谢的重新编程。肿瘤细胞葡萄糖代谢重编程即在氧气存在的情况下肿瘤细胞更喜欢在细胞质进行糖酵解,称为“Warburg效应”或“有氧糖酵解”。肿瘤微环境成分如肿瘤相关成纤维细胞、巨噬细胞、免疫细胞等也可发生糖代谢重编程,且两者之间相互影响促进乳腺癌的发展。全文综述了微环境主要成分与肿瘤细胞葡萄糖代谢重新编程相互作用对乳腺癌生物学和进展的重要性。     

肿瘤代谢重编程及其与肠道菌群关系的研究进展

肿瘤发生、发展过程中,其代谢表型通常会发生改变.除了传统营养物质(葡萄糖、脂质、谷氨酰胺)来源的代谢重编程外,乳酸、乙酸、酮体、外源蛋白质等也能被肿瘤细胞重新摄取利用.健康的肠道菌群维持着体内稳态和肠道正常功能,在调控宿主能量代谢、促进食物消化以及调节免疫等方面有着重要的生理意义.然而肠道菌群的代谢产物能够重塑肿瘤营养...     

肿瘤微环境中代谢检查点调节T细胞免疫功能的研究进展

免疫疗法的出现改变了现有的晚期肿瘤治疗模式,为患者带来了希望。然而,许多肿瘤已经显示出对检查点抑制等免疫治疗的显著抵抗机制,导致部分患者的应答率始终不高,甚至超进展。通过对新兴免疫代谢领域的研究发现,靶向代谢途径重塑肿瘤微环境有望重振抗肿瘤免疫反应,并可能与现有免疫疗法产生协同效应。本文着重探讨了代谢检查点调节T细胞代谢在肿瘤免疫治疗中产生的一系列影响,旨在为肿瘤免疫治疗提供新的思路。     

胰腺癌与支链氨基酸代谢重编程的研究进展

胰腺癌是一种预后极差的消化系统恶性肿瘤,代谢重编程是胰腺癌的显著特征之一.胰腺癌中最常见的KRAS基因突变通过一系列信号通路调控支链氨基酸代谢发生特异性改变.支链氨基酸转氨酶和支链酮酸脱氢酶等支链氨基酸代谢酶的异常表达在胰腺癌的发生和发展中发挥重要作用.循环支链氨基酸浓度的异常升高可以作为胰腺癌早期诊断的重要标志物.本...     

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。     

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。     

Evaluating prognostic value and relevant gene signatures of tumor microenvironment characterization in esophageal carcinoma

BackgroundTumor microenvironment (TME) cells are an important part of tumor tissues. There is increasing evidence that the TME plays a vital role in tumor prognosis, and is associated with patient survival in various kinds of malignances. To date, very little research has been conducted on how to effectively use TME to better evaluate the prognosis of patients with esophageal carcinoma (EC). The concept of a “TME score” was introduced to better distinguish the prognosis of patients.MethodsWe employed bioinformatic methods to investigate the TME infiltration patterns of 160 patients with EC from the Cancer Genome Atlas (TCGA) cohort. TME clusters were identified using k-means clustering methods with 1,000 resampling times. The significance of the survival difference among patients belonging to different TME clusters was assessed by the log-rank test and Kaplan-Meier survival curves. Correlations between immune cell types and survival were calculated by a Cox regression, and the Pearson correlation coefficient (PCC) was used to measure the relationship among different immune cell types. We classified patient into 2 subtypes based on the optimal breakpoint of TME score determined by R package maxstat.ResultsTwo TME phenotypes were defined based on the immune cell type fractions, and patients with a high TME score phenotype had a better prognosis than those with a low TME score phenotype. Kaplan-Meier analysis for differentially expressed micro ribonucleic acids (RNAs) and messenger RNAs also showed that different TME score subtypes were significantly associated with the prognosis of EC. Just as tumor mutational burden can predict the efficacy of immunotherapy, the TME score can predict the efficacy of immune checkpoint inhibitors (ICIs). The genomic alterations of 2 TME score subtypes of EC further revealed that genomic instability is prevalent in TMEs, and patients with a low TME score subtype have a more unstable chromosome status than those with a high subtype.ConclusionsThus, TME score is an emerging prognostic biomarker for predicting the efficacy of ICIs.     

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.     

胃肠道间质肿瘤：微环境特点及免疫治疗思路

胃肠道间质肿瘤(GIST)是胃肠道最常见的间充质来源的肿瘤,对放化疗敏感性低。近二十年来,以伊马替尼为代表的酪氨酸激酶抑制剂类药物在很大程度上改善了GIST患者的预后,但仍有相当数量的患者出现原发或继发性耐药,因此需要开拓新的治疗方法。随着肿瘤免疫治疗的基础与临床研究的进展,越来越多的肿瘤患者从免疫治疗中获益。但是,免疫治疗在GIST中的应用却较为缓慢。目前,免疫检查点抑制剂治疗在GIST中的应用取得了初步进展,未来还需要有更多的循证证据。在发展迅速的免疫细胞疗法和肿瘤疫苗领域,目前尚无相关新技术用于GIST的临床研究。尽管如此,GIST的免疫微环境具有丰富的免疫细胞浸润,提示GIST是潜在的免疫治疗优势病种。但是,免疫治疗在GIST中的应用不能“照搬”上皮来源肿瘤的特征,必须在充分了解GIST免疫特征的基础上,进行针对性研究,开发出基于GIST的免疫治疗策略,才能使免疫治疗真正改善患者的预后。     

COX-2/PGE2在肿瘤发生发展和重塑肿瘤微环境中的研究进展

癌症相关炎症(cancer-related inflammation,CRI)在癌症的发生发展中发挥重要作用,前列腺素E2(prostaglandin E2,PGE2)是炎症环境中最为丰富的类花生酸脂质,也是肿瘤微环境中具有免疫调节功能的脂类代谢产物。目前,PGE2合成途径阻断药物联合抗肿瘤药物在肿瘤治疗方面取得一定成效。因此,了解肿瘤微环境中PGE2合成途径的调控环节及其对肿瘤发生发展的作用机制,可为肿瘤防治找寻新方向、提供新靶点。本文就近年来PGE2在肿瘤发生发展和重塑微环境的研究进展进行概述。     

The role of tumor-infiltrating B cells in the tumor microenvironment of hepatocellular carcinoma and its prognostic value: a bioinformatics analysis

BackgroundAccumulating evidence indicates that tumor heterogeneity is characterized by distinct immunosubtypes. However, prior studies have mainly focused on the functions of T cells. The role of tumor-infiltrating B cells in the microenvironment of hepatocellular carcinoma (HCC) requires further investigation.MethodsWe conducted an integrative analysis of single cell RNA sequencing (scRNA-seq) datasets in HCC tumor samples from Gene Expression Omnibus database. We analyzed the features of B cells in normal liver tissue and HCC. Additionally, we conducted a deconvolution analysis using the matrix of scRNA-seq datasets and the RNA-seq datasets in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database. The survival analyses of the TCGA-LIHC cohort with different B cell infiltration rates and was further validated. Finally, we performed immunohistochemistry analysis of primary tumor tissue of HCC patients using antibodies against CD79A and validated the impact of tumor-infiltrating B cells in the prognosis of LIHC.ResultsWe identified several subtypes of B cells in the microenvironment of HCC, including the plasma cells and naïve B cells. The relative ratio of B cells, but not the plasma cells, was significantly decreased in HCC as compared to the normal liver tissue (P<0.05). In addition, genes related to antigen presentation and cell proliferation were decreased in tumor-infiltrating B cells (P<0.05). The observation of B cell infiltration was further validated with the TCGA-LIHC cohort. The overall survival and disease-free survival in HCC patients with higher B-cell infiltration rate were significantly longer than those in the lower infiltration group (P<0.05) in the TCGA-LIHC cohort. Moreover, we demonstrated higher infiltration rates of B cells were significantly associated with a better prognosis of HCC in our cohort.ConclusionsTumor-infiltrating B cells potentially exert a tumor-suppressive function in the microenvironment of HCC and the higher levels of B cell infiltration are associated with a favorable outcome of HCC. Targeted activation of B cells may improve the tumor immune-targeted therapy.     

Myeloid derived suppressor cells in cancer,premalignancy and inflammation: A roadmap to cancer immunoprevention

The ultimate success of any form of cancer therapy or cancer prevention depends on its ability to engage the power of the immune system to completely eliminate a growing tumor, lower the life-time tumor risk and establish long-term memory to prevent recurrence or future tumors. For that reason, all therapies but especially immunotherapies depend on the immune health (immunocompetence) of each treated individual. Cancer and chronic illnesses, combined with a usually more advanced age of cancer patients or those at risk for cancer are known to severely suppress multiple antitumor functions of the immune system. Understanding the critical mechanisms controlling and mediating immune suppression can lead to additional therapies to alleviate the effects of those mechanisms and improve the outcome of cancer therapy and prevention. We introduce and review here a highly immunosuppressive cell population found in cancer, precancer, and chronic inflammatory diseases, myeloid derived suppressor cells (MDSC). First described in the setting of advanced cancer, their presence and immunosuppressive activity has been seen more recently in early premalignant lesions and in chronic inflammatory diseases leading to cancer. We describe the detrimental effects of their presence on cancer immunotherapy, immunosurveillance and immunoprevention and review early attempts to develop drugs to eliminate them or reduce their negative impact.