全身热疗与肿瘤免疫的研究进展

提高全身和/或肿瘤局部温度,利用热及其继发效应来到达治疗作用,称为肿瘤热疗（Hyperthermia）.热疗的抗肿瘤作用不仅在于高热直接杀死肿瘤细胞,机体免疫状态的改变也对消灭肿瘤起着重要作用.     

肿瘤局部热疗与免疫

肿瘤局部热疗后免疫状态的改变，对热疗的效果具有重要的影响。热疗后主要表现为细胞免疫功能增强，最重要的是ＮＫ细胞，Ｔ淋巴细胞的活性增强，可能是通过肿瘤变性蛋白刺激机体的免疫系统，也可能是热疗后瘤细胞抗原性增加所致。     

热疗对肿瘤微环境中肿瘤相关成纤维细胞作用的研究进展北大核心CSCD

肿瘤微环境具有免疫抑制特性,其作用机制是诱导肿瘤细胞的免疫逃逸,它与肿瘤细胞之间的相互作用是影响肿瘤发生发展的重要因素。肿瘤相关成纤维细胞是肿瘤微环境的一个重要组成部分,其主要功能是与肿瘤细胞发生直接或间接的相互作用,并产生各种细胞因子,从而对肿瘤免疫微环境起到调节作用。肿瘤热疗作为抗肿瘤治疗的一种手段,随着对肿瘤热疗和肿瘤微环境的研究不断深入,大量研究发现热疗对肿瘤微环境中的肿瘤相关成纤维细胞具有多种调节功能。本文结合国内外最新研究进展,阐述热疗对肿瘤微环境中肿瘤相关成纤维细胞及其相关细胞和因子的影响,为肿瘤热疗结合免疫或靶向治疗的临床应用提供新途径。     

热疗对肿瘤微环境中肿瘤相关成纤维细胞作用的研究进展

肿瘤微环境具有免疫抑制特性, 其作用机制是诱导肿瘤细胞的免疫逃逸, 它与肿瘤细胞之间的相互作用是影响肿瘤发生发展的重要因素。肿瘤相关成纤维细胞是肿瘤微环境的一个重要组成部分, 其主要功能是与肿瘤细胞发生直接或间接的相互作用, 并产生各种细胞因子, 从而对肿瘤免疫微环境起到调节作用。肿瘤热疗作为抗肿瘤治疗的一种手段, 随着对肿瘤热疗和肿瘤微环境的研究不断深入, 大量研究发现热疗对肿瘤微环境中的肿瘤相关成纤维细胞具有多种调节功能。本文结合国内外最新研究进展, 阐述热疗对肿瘤微环境中肿瘤相关成纤维细胞及其相关细胞和因子的影响, 为肿瘤热疗结合免疫或靶向治疗的临床应用提供新途径。     

临床肿瘤热疗的几点思考

肿瘤热疗已经从热对药物增敏，热对放射增敏的研究走出。近年来全身热疗引起机体免疫的研究逐渐深入，热休克蛋白-肿瘤抗原肽疫苗的开发和初步应用，对临床热疗的方案设计将会有很大的改变。作者对肿瘤热疗特别是全身热疗的发展，提出个人见解。     

热疗联合免疫检查点抑制剂的基础研究和临床应用进展北大核心CSCD

恶性肿瘤传统治疗方法对晚期转移患者疗效欠佳。近年来免疫检查点抑制剂治疗发展迅速,极具潜力,但整体临床有效率不高。肿瘤通过多种机制改变肿瘤微环境,产生免疫耐药,从而大大降低了免疫检查点抑制剂的疗效。热疗不仅可发挥热效应的抗肿瘤优势,还可通过多种途径起到直接和间接免疫增敏作用,将"冷肿瘤"转变为"热肿瘤",从而多方面起到增强免疫检查点抑制剂疗效的作用。大量基础实验证明,在小鼠体内进行热疗联合免疫检查点抑制剂已取得较好效果。目前,部分正在开展的热疗联合免疫检查点抑制剂临床试验也已取得较好进展。本文从免疫检查点抑制剂、热疗、热疗联合免疫检查点抑制剂3个层面分析了联用优势,并展望了未来热疗联合免疫检查点抑制剂治疗的重点研究方向。     

肿瘤热疗与抗肿瘤免疫的研究进展

近年来,随着肿瘤综合治疗的发展,热疗已成为治疗癌症的重要手段之一。大量研究表明,肿瘤细胞的清除,一方面取决于外在的治疗手段,另一方面取决于人体自身的抗肿瘤免疫状态。热疗不仅能直接杀死肿瘤细胞,还能激活人体的免疫力从而发挥抗肿瘤作用。近年来,随着肿瘤研究的深入,肿瘤热疗与抗肿瘤免疫的机制及其在临床上的应用引起了人们的兴趣,并成为一个新的研究领域。本文将肿瘤热疗与抗肿瘤免疫之间的研究进展作一综述。     

肿瘤热疗机制的研究进展

热疗对肿瘤细胞具有直接杀伤作用,并可诱导其凋亡,而细胞凋亡过程受一系列相关基因的调控,其中野生型p53、Fas、bcl-2、突变型p53、c-mye、c-fos等基因与之关系密切。热疗还可以破坏肿瘤血管,使其数量减少,并且通过改变基质金属蛋白酶（MMP）和黏附因子的表达抑制肿瘤的侵袭和转移。热疗可以上调机体的抗肿瘤免疫功能,但其机制目前尚未完全明了。全文主要从以上几方面对肿瘤热疗作用机制的研究进展作一综述。     

热疗及热休克蛋白对肿瘤免疫应答的影响

热疗是一种利用人为诱导发热生物学效应的抗肿瘤治疗方法,其通过联合放化疗来增强机体抗肿瘤的疗效已被多项研究证实.越来越多的研究证实,热疗可以通过导致热休克蛋白(HSP)水平升高来促使抗原呈递细胞对抗原的摄取和呈递;诱导T细胞的增殖、分化并向肿瘤组织转移和浸润;增强T细胞对肿瘤细胞的杀伤作用等多方面免疫效应来提高抗肿瘤疗效.本文总结了热疗和HSP对肿瘤先天性及获得性免疫应答的影响,旨在为热疗临床及基础相关研究提供指导.     

肿瘤热疗生物学机制研究进展

近年来肿瘤热疗主要作为肿瘤传统治疗的辅助疗法成为研究热点。热疗可直接诱导肿瘤细胞坏死或凋亡,或通过破坏肿瘤血管抑制其进展,同时热疗还能激活机体免疫系统的免疫细胞和细胞因子的反应,从而调节肿瘤微环境的免疫状态。多种效应相联合共同影响肿瘤的进展。深入了解肿瘤热疗的生物学机制有利于开展新的治疗方法,本文主要对热疗杀灭肿瘤的生物学机制做一综述。     

Effect of hyperthermia on immune cells and immune-related cytokines in tumor immune microenvironment

With the in-depth study of tumor hyperthermia and tumor immune microenvironment (TIME), the role of hyperthermia in TIME has captivated increasing attention from scholars in recent years. Based upon recent research progress at home and abroad, the effect and mechanism of hyperthermia on several major immune cells and immune-related cytokines in the TIME were reviewed in this article. Comprehensive and deep understanding of the regulation of hyperthermia on the TIME could provide new ideas and methods for tumor treatment.     

T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy

Hepatocellular carcinoma (HCC) is characterized by poor outcome and shows limited drug-response in clinical trials. Tumor immune microenvironment (TIME) exerts a strong selection pressure on HCC, leading to HCC evolvement and recurrence after multiple therapies. T cell-mediated immunoreaction during cancer surveillance and clearance is central in cancer immunity. Heterogenous T cell subsets play multiple roles in HCC development and progression. The re-educated T cells in TIME usually lead to deteriorated T cell response and tumor progression. Investigation into immune system dysregulation during HCC development will shed light on how to turn immune suppressive state to immune activation and induce more efficient immune response. Emerging T cell-based treatment such as cancer vaccines, CAR-T cell therapy, adoptive cell therapy, and immune checkpoint inhibitors (ICIs), have been proved to cause tumor regression in some clinical and preclinical trials. In this review, we focused on recent studies that explored T cells involved in HCC and how they affect the course of disease. We also briefly outlined current T cell-based immunotherapies in HCC.     

Hyperthermia on immune regulation: a temperature's story

Over the last decade the linkage between hyperthermia, heat shock proteins and fever with the body's immune system has been well investigated. The immunomodulatory function of hyperthermia has been found to be quite sensitively regulated by temperature, as different levels of heating can bring different modulatory effect on different sensitive targets. Understanding these intrinsic mechanisms could bring new inspirations on the design of clinical trials combining local tumor hyperthermia with immunotherapy in cancer patients. This review will attempt to tell the story about the effect of temperature on immune regulation, with special emphasis on the clinical application of hyperthermia and the feasibility of combining it with immunotherapy in the clinic.     

Does whole-body hyperthermia therapy involve participation of the immune system?

The effect of micro-wave whole-body hyperthermia on tumor growth and lung metastasis counts was examined in adult BALB/c mice. The effective therapy with hyperthermia prolonging mean survival time of the animals and causing tumor regression resulted in concomitant depression of anti-tumor immunity measured in vivo. The beneficial effect of preimmunization of animals with killed tumor cells on subsequent challenge with live tumor cells was completely abrogated by hyperthermia treatment. It is postulated that this form of therapy is directly related only to heat sensitivity of tumor cells and that there is no profitable participation of the immune system in the anti-tumor effect of wholebody hyperthermia.     

How is the immune response affected by hyperthermia and heat shock proteins?

There is growing body of evidence linking the cellular response to heat stress with the response of the immune system to cancer. The anti-tumor immune response can be markedly enhanced by treatment with hyperthermia particularly in the fever range. In addition, the heat shock proteins (hsp) which are produced in abundant quantities in cells exposed to heat are potent immune modulators and can lead to stimulation of both the innate and adaptive immune responses to tumors. Immunostimulation by hyperthermia involves both direct effects of heat on the behavior of immune cells as well as indirect effects mediated through hsp release. In addition, the hsp can be deployed as components of antitumor vaccines in protocols that do not include hyperthermia. Understanding these process may permit the effective deployment of hyperthermia and hsp based vaccines in tumor treatment.     

New Strategies and Combinations to Improve Outcomes in Immunotherapy in Metastatic Non-Small-Cell Lung Cancer

Immune checkpoint inhibitors have transformed the treatment of metastatic non-small-cell lung cancer, yielding marked improvements in survival and the potential for durable clinical responses. Primary and acquired resistance to current immune checkpoint inhibitors constitute a key challenge despite the remarkable responses observed in a subset of patients. Multiple novel combination immunotherapy and adoptive cell therapy strategies are presently being developed to address treatment resistance. The success of these strategies hinges upon rational clinical trial design as well as careful consideration of the immunologic mechanisms within the variable tumor immune microenvironment (TIME) which underpin resistance to immunotherapy. Further research is needed to facilitate a deeper understanding of these complex mechanisms within the TIME, which may ultimately provide the key to restoring and enhancing an effective anti-tumor immune response. This review aims to provide an introduction to some of the recent and notable combination immunotherapy and cell therapy strategies used in advanced non-small-cell lung cancer (NSCLC), and the rationale for their use based on current understanding of the anti-tumor immune response and mechanisms of resistance within the TIME.     

Suppressed immune microenvironment and repertoire in brain metastases from patients with resected non-small-cell lung cancer

BackgroundThe tumor immune microenvironment (TIME) of lung cancer brain metastasis is largely unexplored. We carried out immune profiling and sequencing analysis of paired resected primary tumors and brain metastases of non-small-cell lung carcinoma (NSCLC).Patients and methodsTIME profiling of archival formalin-fixed and paraffin-embedded specimens of paired primary tumors and brain metastases from 39 patients with surgically resected NSCLCs was carried out using a 770 immune gene expression panel and by T-cell receptor beta repertoire (TCRβ) sequencing. Immunohistochemistry was carried out for validation. Targeted sequencing was carried out to catalog hot spot mutations in cancer genes.ResultsSomatic hot spot mutations were mostly shared between both tumor sites (28/39 patients; 71%). We identified 161 differentially expressed genes, indicating inhibition of dendritic cell maturation, Th1, and leukocyte extravasation signaling pathways, in brain metastases compared with primary tumors (P < 0.01). The proinflammatory cell adhesion molecule vascular cell adhesion protein 1 was significantly suppressed in brain metastases compared with primary tumors. Brain metastases exhibited lower T cell and elevated macrophage infiltration compared with primary tumors (P < 0.001). T-cell clones were expanded in 64% of brain metastases compared with their corresponding primary tumors. Furthermore, while TCR repertoires were largely shared between paired brain metastases and primary tumors, T-cell densities were sparse in the metastases.ConclusionWe present findings that suggest that the TIME in brain metastases from NSCLC is immunosuppressed and comprises immune phenotypes (e.g. immunosuppressive tumor-associated macrophages) that may help guide immunotherapeutic strategies for NSCLC brain metastases.