放疗对机体抗肿瘤免疫效应机制的影响

放疗主要通过对放射野内肿瘤细胞的杀伤使靶区内肿瘤得到控制、可以作用于远处转移灶并能够激活机体抗肿瘤免疫应答。越来越多的研究表明合理的放疗剂量和分割模式能够改善肿瘤微环境,诱导特异性 T 细胞免疫应答,形成原位疫苗并激活机体的抗肿瘤免疫效应。本文重点阐述放疗对机体抗肿瘤免疫效应机制的影响,以及放疗在免疫治疗的辅助下如何发挥抗肿瘤的作用,为恶性肿瘤治疗提供新思路。     

放疗与肿瘤免疫

肿瘤微环境中的免疫细胞和细胞因子在抗肿瘤免疫中具有不同功能。放疗可通过放射生物效应杀伤肿瘤细胞,同时还能间接改变肿瘤免疫微环境,协同产生局部或远处抗肿瘤免疫效应。放疗联合免疫治疗的动物和临床试验证实其良好的应用前景,联合治疗时具体的放射治疗模式尚需进一步研究。     

放射治疗联合免疫疗法治疗恶性肿瘤的相关机制与研究进展

放射治疗能通过诱导 DNA 损伤杀伤照射野内的肿瘤细胞,也能激活机体免疫系统。放疗可促进肿瘤相关抗原释放、激活树突状细胞并促进肿瘤相关抗原的呈递、增加肿瘤浸润淋巴细胞,刺激免疫系统阻止肿瘤的复发和（或）转移。一些研究已证实放疗与免疫治疗联合可发挥协同抗肿瘤效应。本文就放疗与免疫治疗联合应用抗肿瘤的相关机制及最新研究进展做一综述。     

放疗联合免疫治疗的相关机制及研究进展

近年来,恶性肿瘤的发病率越来越高,而肿瘤的各种治疗技术也在不断提高,治疗方案不断完善。放疗主要是通过放射线对局部肿瘤细胞的杀伤来达到治疗效果,而在放疗过程中,可以诱导或提高抗肿瘤免疫反应。合适的放疗剂量、分割模式联合一定的免疫治疗在肿瘤的治疗中越来越起到重要的作用。本文综述了放疗增强抗肿瘤免疫反应的相关机制及放疗联合免疫治疗研究现状和发展前景。     

放疗免疫调节效应研究的进展——从基础到临床

既往观点认为，放射治疗主要通过破坏肿瘤细胞脱氧核糖核酸双链直接发挥杀伤肿瘤细胞的作用，近年来研究发现，放疗也可通过上调局部与全身免疫反应，间接产生积极有效的抗肿瘤免疫应答。然而，放疗的免疫调节效应具有双面性，一方面可激活并产生抗肿瘤免疫促进效应，另一方面也可能产生免疫抑制作用。其中，放疗正向调节适应性与固有性抗肿瘤免疫反应的关键分子机制主要包括：诱导免疫原性细胞凋亡从而促进T淋巴细胞的增殖与活化；激活环磷酸鸟苷-腺苷合成酶-干扰素基因刺激蛋白通路引发Ⅰ型干扰素反应；改变肿瘤细胞表型，加强其免疫原性与抗原可视度；刺激肿瘤细胞与基质细胞释放多种炎症因子，重塑肿瘤免疫微环境；上调肿瘤细胞表面免疫检查点以及死亡受体等的表达，促进免疫识别与抗肿瘤免疫应答。而放疗负向抑制免疫反应的主要机制包括：诱导肿瘤细胞上调多种免疫抑制因子的基因表达；增强包括调节性T细胞、髓系来源抑制性细胞在内的多种免疫抑制细胞的功能与作用；导致淋巴细胞的数量减少以及免疫效应细胞的耗竭等。基于以上关于放疗免疫调节效应的机制原理探索，目前在放疗联合免疫治疗的临床实践中也显示出重大的研究进展，包括免疫治疗时代背景下的放疗远隔效应，...     

放疗联合免疫治疗癌症的研究进展

放疗不仅是肿瘤局部治疗的重要手段,同时也对免疫功能有重要的调节作用。放疗可通过产生新抗原、调节细胞因子释放、提高肿瘤对免疫细胞杀伤作用敏感性等方式调节机体抗肿瘤免疫应答。近年来部分研究和临床实践发现,放疗联合免疫治疗在部分病例中出现“远位效应”,照射野范围外的转移性病灶有部分或完全缓解,显示放疗联合免疫治疗的良好前景;但相关机制以及放疗剂量、分割方式等因素对免疫的影响仍有待进一步研究。本文综述了放疗影响免疫的机制以及放疗联合免疫治疗的研究进展。     

局部晚期宫颈癌放疗结合免疫治疗的相关研究进展

局部晚期宫颈癌患者标准治疗方案为同步放化疗,短期疗效较好,但远期预后较差,易局部复发和远处转移,严重影响患者的生活质量及总生存期.近年来,免疫治疗成为国内外学者研究的热点,其可以激活机体自身的免疫系统,通过增强体内免疫细胞的数量及功能,从而特异性、持续地识别并消灭肿瘤细胞.放疗主要是对照射野内的肿瘤组织采用高能射线的方式精确杀死局部肿瘤组织,死亡后的肿瘤组织最终作为一种新抗原激活体内的抗肿瘤免疫反应.基于局部放疗与免疫系统的内在协同作用使放疗结合免疫治疗成为可能.本文就国内外在局部晚期宫颈癌放疗结合免疫治疗的广阔前景及面临的相关挑战进行综述.     

放疗联合免疫治疗的生物学基础及研究进展

研究发现放疗能促进肿瘤细胞免疫原性死亡，并经肿瘤抗原呈递和特异性T细胞免疫应答过程来杀伤肿瘤，甚至产生系统性抗肿瘤免疫反应，引起照射野外肿瘤缩小，上述现象被称为放疗远位效应。尽管放疗的临床远位效应已有报道，许多基础及转化性研究也证实其发生存在一定的生物学基础，但放疗远位效应更多地表现为亚临床效应，难以达到临床客观疗效。目前，抗PD-1/PD-L1抗体免疫治疗在临床肿瘤研究中展示出明显而确切的疗效，是临床中局部放疗联合免疫治疗的新治疗模式。但是，这种新治疗模式的临床实践，应当基于能够产生远位效应的放疗分割模式以及最佳的联合时机，最终达到全身抗肿瘤免疫反应的协同疗效。      

补体系统与肿瘤免疫的研究进展

补体系统是先天免疫反应的重要组成部分,但其生物学意义远远超出了简单的非特异性防御。在肿瘤微环境中,补体系统对肿瘤的发生、发展起着双重调控作用,影响免疫应答的结果。通过对免疫系统的调节以及对肿瘤细胞的直接杀伤作用,补体促进了免疫监视并抑制肿瘤进展;然而,过度激活的补体可以通过多种途径影响宿主免疫反应,是炎症、免疫抑制和肿瘤进展之间的重要环节。在抗肿瘤免疫治疗过程中靶向补体系统有助于克服免疫抑制,产生抗肿瘤免疫反应。本文对补体系统与肿瘤免疫的研究进展进行综述,旨在为抗肿瘤免疫治疗提供选择。      

SBRT联合免疫治疗的机制及研究进展

近年来,大量临床前和临床研究表明,SBRT除直接杀伤肿瘤细胞外,还能导致肿瘤细胞免疫原性死亡,释放大量肿瘤相关抗原(TAA)及危险相关模式分子(DAMPs)形成肿瘤原位疫苗。通过激活的抗原提呈细胞交叉致敏引流淋巴结内的CD8(+) T细胞。SBRT能介导肿瘤局部和全身系统性的抗肿瘤免疫反应,与免疫治疗结合,还可以引发远位效应。SBRT同时能改善肿瘤免疫抑制微环境,增加肿瘤对免疫治疗的敏感性。本文对SBRT联合肿瘤免疫治疗的协同作用机制的研究进展进行综述。     

Is There a Benefit of Combining Immunotherapy and Radiotherapy in Bladder Cancer?

Immune checkpoint inhibitors have transformed the management of patients with metastatic urothelial cancer, by leading to long-term response and prolongation of survival in a subset of patients. Unfortunately, only one in five patients with metastatic urothelial cancer responds to anti-programmed death ligand-1 ([AQ1]anti-PD-1) monotherapy. Preclinical and early clinical evidence indicates that radiotherapy not only acts locally, but also exerts systemic anti-tumour effects by modulating the immune system. It is hypothesised that combining checkpoint inhibitors with radiotherapy might enhance an anti-tumour immune response and increase response rates. So far, a handful of early phase clinical trials have been performed seeking to answer this question in urothelial cancer patients. The current review summarises the available preclinical and clinical evidence on radiotherapy/immunotherapy combinations in locally advanced and metastatic bladder cancer and suggests future avenues worthy of exploration.     

The Abscopal Effect in the Era of Cancer Immunotherapy: a Spontaneous Synergism Boosting Anti-tumor Immunity?

Radiotherapy is one of the main treatment strategies used in cancer. Aside from the local control of the disease, which is mediated by a direct cytotoxic effect on tumor cells, radiotherapy has also been shown to exert immune-mediated local and systemic effects. Radiotherapy can elicit anti-tumor responses in distant sites from the radiation field; this phenomenon is known as the abscopal effect and has been described in patients previously treated with immune checkpoint blockade (ICB). Considering that the efficacy of immunotherapy has been demonstrated only in a subset of patients—who often benefit with lasting responses—efforts are ongoing to potentiate its activity with the development of new combination strategies. Radiotherapy might represent a potential candidate for a synergistic combination with immunotherapy, by improving the immunogenicity of tumors and by enhancing local and systemic immune effects. This review aims to summarize the current pre-clinical and clinical data on the immune effects of radiotherapy and their potential implications for cancer immunotherapy.

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靶向免疫治疗联合放射治疗在晚期黑色素瘤中的研究进展

黑色素瘤是皮肤癌中最具侵袭性、死亡率较高的恶性肿瘤。Ⅰ、Ⅱ期黑色素瘤采取手术切除可完全治愈,Ⅲ、Ⅳ期黑色素瘤应用传统的手术、放化疗方案治疗效果不理想,预后差。近年来,随着对Ⅲ、Ⅳ期黑色素瘤治疗方案的探索,靶向免疫治疗取得了显著疗效。靶向免疫药物可抑制负性调节因子,增强全身抗肿瘤免疫效应。放疗在杀死局部肿瘤的同时,也可增强全身免疫应答。近期研究发现,靶向免疫联合放射治疗可增强对肿瘤局部和远处的控制作用,延长患者总体生存期,两者联合治疗优于单一治疗方案。本文对上述研究领域内的进展进行综述。      

Clinical Trials Integrating Immunotherapy and Radiation for Non–Small-Cell Lung Cancer

Methods of harnessing the immune system to treat cancer have been investigated for decades, but yielded little clinical progress. However, in recent years, novel drugs that allow immune recognition and destruction of tumor cells are emerging as potent cancer therapies. Building upon previous immunotherapy strategies that included therapeutic vaccines, recombinant cytokines, and other immunostimulatory agents, newer immunotherapy agents targeting immune checkpoints including programmed cell death 1, programmed cell death ligand-1, and cytotoxic T-lymphocyte-associated protein 4, among others, have garnered substantial enthusiasm after demonstrating clinical activity in a broad spectrum of tumor types. Trials evaluating immune checkpoint inhibitors in metastatic non–small-cell lung cancer (NSCLC) demonstrate robust and durable responses in a subset of patients. However, with overall response rates less than 20%, combinatorial strategies that extend the benefit of these agents to more patients are desirable. The integration of radiotherapy with immunotherapy is a conceptually promising strategy, as radiotherapy has potent immunomodulatory effects and may contribute not only to local control but may also augment systemic antitumor immune response. Preclinical data and case reports suggest the potential for robust clinical responses in metastatic NSCLC patients using this strategy, but prospective clinical trials evaluating the integration of radiation and immunotherapy are limited. The use of immunotherapy in nonmetastatic settings is also intriguing but understudied. We review the potential clinical settings of interest for the partnering of immunotherapy and radiation in NSCLC, including early stage, locally advanced, and metastatic disease, and review completed, accruing, and developing clinical trials.     

Radiotherapy combination opportunities leveraging immunity for the next oncology practice

Approximately one‐half of patients with newly diagnosed cancer and many patients with persistent or recurrent tumors receive radiotherapy (RT), with the explicit goal of eliminating tumors through direct killing. The current RT dose and schedule regimens have been empirically developed. Although early clinical studies revealed that RT could provoke important responses not only at the site of treatment but also on remote, nonirradiated tumor deposits—the so‐called “abscopal effect”— the underlying mechanisms were poorly understood and were not therapeutically exploited. Recent work has elucidated the immune mechanisms underlying these effects and has paved the way for developing combinations of RT with immune therapy. In the wake of recent therapeutic breakthroughs in the field of immunotherapy, rational combinations of immunotherapy with RT could profoundly change the standard of care for many tumor types in the next decade. Thus, a deep understanding of the immunologic effects of RT is urgently needed to design the next generation of therapeutic combinations. Here, the authors review the immune mechanisms of tumor radiation and summarize the preclinical and clinical evidence on immunotherapy‐RT combinations. Furthermore, a framework is provided for the practicing clinician and the clinician investigator to guide the development of novel combinations to more rapidly advance this important field. CA Cancer J Clin 2017;67:65–85. © 2016 American Cancer Society .     

The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors

Therapeutic cancer vaccines are a unique treatment modality in that they initiate a dynamic process of activating the host immune system, which can then be exploited by concurrent or subsequent therapies. The addition of immunotherapy to standard-of-care cancer therapies has shown evidence of efficacy in preclinical models and in the clinical setting. This review examines the preclinical and clinical interactions between vaccine-mediated tumor-specific immune responses and local radiation, systemic chemotherapy, or select small molecule inhibitors, as well as the potential synergy between these modalities.     

Radio‐responsive tumors exhibit greater intratumoral immune activity than nonresponsive tumors

Radiation therapy (RT) continues to be a cornerstone in the treatment for many cancers. Unfortunately, not all individuals respond effectively to RT resulting clinically in two groups consisting of nonresponders (progressive disease) and responders (tumor control/cure). The mechanisms that govern the outcome of radiotherapy are poorly understood. Interestingly, a new paradigm has emerged demonstrating that the immune system mediates many of the antitumor effects of RT. Therefore, we hypothesized that the immune response following RT may dictate the efficacy of treatment. To examine this, we developed a tumor model that mirrors this clinically relevant phenomenon in which mice bearing Colon38, a colon adenocarcinoma, were treated locally with 15Gy RT resulting in both nonresponders and responders. More importantly, we were able to distinguish responders from nonresponders as early as 4 days post‐RT allowing for the unique opportunity to identify critical events that ultimately determined the effectiveness of therapy. Intratumoral immune cells and interferon‐gamma were increased in responsive tumors and licensed CD8 T cells to exhibit lytic activity against tumor cells, a response that was diminished in tumors refractory to RT. Combinatorial treatment with RT and the immunomodulatory cytokine IL‐12 resulted in complete remission of cancer in 100% of cases compared to a cure rate of only 12% with RT alone. Similar data were obtained when IL‐12 was delivered by microspheres. Therefore, the efficacy of RT may depend on the strength of the immune response induced after radiotherapy. Additionally, immunotherapy that further stimulates the immune cells may enhance the effectiveness of RT.     

驱动基因阴性晚期非小细胞肺癌脑转移免疫微环境及免疫治疗的研究进展

远端转移是晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者难以避免的并发症,脑转移（brain metastases,BM）是此类患者最常见的转移部位之一。脑转移患者可能出现头痛、视物模糊、偏瘫、肢体麻木等症状,生存质量受到严重影响。脑转移患者通常预后较差,自然中位生存期仅有3个月左右。传统上,针对驱动基因阴性NSCLC脑转移的治疗策略有局部干预的外科手术、放射治疗及系统性干预的化疗等,而有明确基因突变如EGFR、ALK、ROS1等的患者可采用新一代靶向药物治疗,但两类患者颅内治疗疗效均欠佳。免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）的出现为晚期肺癌的治疗带来新希望,其在黑色素瘤及肺癌脑转移患者中观察到了一定疗效。脑转移瘤的血管与正常脑血管存在显著差异。不同于肺部原发病灶,脑转移瘤具有独特的肿瘤微环境、免疫细胞特征及血管结构,无论是免疫单药治疗还是免疫联合治疗对肺癌脑转移患者均有效。由于难以获得脑组织样本,免疫治疗的生物标志物的研究受到限制。除了肿瘤细胞程序性死亡-配体1（programmed cell death ligand-1,PD-L1）外,肿瘤突变负荷（tumor mutation burden,TMB）可能是预测免疫治疗疗效的潜在生物标志物。本文梳理脑部肿瘤的微环境特征,回顾ICIs治疗相关研究进展,拟为驱动基因阴性NSCLC脑转移患者的治疗提供参考。      

Angiosarcoma of the scalp treated with curative radiotherapy plus recombinant interleukin-2 immunotherapy

PURPOSE: To evaluate the effectiveness of curative radiotherapy (RT) plus recombinant interleukin-2 (rIL-2) immunotherapy regarding the treatment results for angiosarcoma of the scalp. Curative resection of angiosarcoma of the scalp is usually difficult because of the diffuse, clinically undetectable local spread. RT is a rational therapeutic approach, because a wide region of the dermis can be treated, while sparing the underlying normal tissues. Recently, the effectiveness of immunotherapy with rIL-2 has also been reported in the treatment of angiosarcoma of the scalp. METHODS AND MATERIALS: The data of 20 patients with angiosarcoma of the scalp treated with curative RT plus rIL-2 immunotherapy between January 1988 and June 2002 were retrospectively analyzed. The total radiation dose was 70.3 +/- 6.9 Gy. The fractions were 2-3 Gy daily, given 5 d/wk. rIL-2 immunotherapy was performed by transcatheter arterial administration in 10 patients, systemic administration in 11 during the course of RT, and intratumoral injection in 10 during and/or after RT; 12 patients received a combination of two. Five patients underwent limited surgery, and concomitant pacilitaxel chemotherapy was also used in 2 patients. RESULTS: The median survival time for overall, local recurrence-free, and distant metastasis-free survival was 36.2, 11.1, and 17.8 months, respectively. Local recurrence developed in 7 patients (35%), 4 of whom also had evidence of distant metastases. An additional 7 patients (35%) developed distant metastases alone. Recurrence within the radiation field was recognized in 2 patients with systemic rIL-2 administration alone (p < 0.05). Arterial or intratumoral administration combined with systemic administration of rIL-2 resulted in better distant metaststasis-free survival rates (p < 0.05). CONCLUSION: Curative RT plus rIL-2 immunotherapy provided an efficient, effective means of treating angiosarcoma of the scalp. Arterial or intratumoral administration combined with systemic administration of rIL-2 may prolong survival. Additional studies with detailed treatment protocols are recommended.     

食管癌放疗联合免疫治疗作用机制及临床研究进展北大核心CSCD

放射治疗是食管癌综合治疗的主要手段之一,其在免疫系统中具有双重作用,并可以介导全身免疫反应的发生。但放疗诱导的肿瘤杀伤效果有限,联合靶向免疫治疗可以增加远隔效应的发生。现多项临床研究已证明免疫检查点抑制剂(ICIs,如PD-1/L1抗体)在晚期食管癌治疗中的作用和巨大潜力,而放疗和ICIs具有协同作用。目前正在开展的多项同步放化疗联合免疫治疗的研究,有望确定该综合治疗方法在食管癌中的疗效,明确其在提高抗癌治疗的效率和成本效益方面的作用。