Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation - implications for cancer therapies

Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.     

The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives

Tumor microenvironment (TME) includes a wide range of cell types including cancer cells, cells which are involved in stromal structure and immune cells (tumor suppressor and tumor promoting cells). These cells have several interactions with each other that are mainly regulated via the release of intercellular mediators. Radiotherapy can modulate these interactions via shifting secretions into inflammatory or anti-inflammatory responses. Radiotherapy also can trigger resistance of cancer (stem) cells via activation of stromal cells. The main mechanisms of tumor resistance to radiotherapy is the exhaustion of anti-tumor immunity via suppression of CD4+ T cells and apoptosis of cytotoxic CD8+ T lymphocytes (CTLs). Cancer-associated fibroblasts (CAFs), mesenchymal-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are the main suppressor of anti-tumor immunity via the release of several chemokines, cytokines and immune suppressors. In this review, we explain the main cellular and molecular interactions and secretions in TME following radiotherapy. Furthermore, the main signaling pathways and intercellular connections that can be targeted to improve therapeutic efficiency of radiotherapy will be discussed.     

Research progress and clinical prospect of immunocytotherapy for the treatment of hepatocellular carcinoma

As a common malignant tumor, hepatocellular carcinoma (HCC) has high fatality rate due to its strong metastasis and high degree of malignancy. Current treatment strategies adopted in clinical practice were still conventional surgery, assisted with interventional therapy, radiotherapy and chemotherapy. However these treatments have limited effects with high recurrence rate. Current research progress of immunocytotherapy has shown that tumor cells can be directly identified and killed by stimulating the immune function and enhancing the anti-tumor immunity in tumor microenvironment. Targeted immunotherapeutics have therefore become the hope of conquering cancer in the future. It can kill tumor cells without damaging the body's immune system and function, restore and strengthen the body's natural anti-tumor immune system. It can reduce the toxic side effects of radiotherapy and chemotherapy, reduce the recurrence rate and prolong the survival period of patients with HCC. Currently, the immune cells widely studied are mainly as follows: Dendritic cells (DC), Cytokine-induced killer (CIK), DC-CIK, Chimeric antigen receptor T cells (CAR-T), Tumor infiltrating lymphocyte (TIL) and Natural killer cell (NK). Immunocytotherapy is a long-term treatment method, some studies have combined traditional therapy with immunocytotherapy and achieved significant effects, providing experimental basis for the application of immunocytotherapy. However, there are still some difficulties in the clinical application of immune cells. In this article, we discuss the application of immunocytotherapy in the clinical treatment of HCC, their effectiveness either alone or in combination with conventional therapies, and how future immunocytotherapeutics can be further improved from investigations in tumour immunology.     

The therapeutic efficacy of angiostatin against weakly- and highly-immunogenic 3LL tumors

BACKGROUND: Antiagiogenesis represents a promising approach to cancer therapy. We have previously demonstrated that the antitumor effects of endostatin, one of the most potent angiostatic agents, could be enhanced when combined with immunotherapy. Our current study evaluated whether anti-tumor immune response could also potentiate the therapuetic efficacy of another antiangiogenic drug, angiostatin. METHODS AND RESULTS: Using Matrigel assay, we showed that our preparation of recombinant angiostatin possessed potent anti-angiogenic activity in vivo. The antitumor effects of recombinant angiostatin were tested against weakly-immunogenic 3LL Lewis lung carcinoma versus its highly immunogenic variant 3LL-C75. We showed that angiostatin inhibited the growth of 3LL-C75 more potently than that of 3LL tumor, suggesting that the host's immune response potentiates the antitumor effects of angiostatin. This conclusion was further supported by the finding that the antitumor activity of angiostatin against 3LL-C75 tumor was lower in immunodeficient nude mice in comparison with immunocompetent mice. Immunization of C57BL/6 mice with 3LL-C75 cells stimulated the antitumor immunity and inhibited the growth of parental 3LL tumor. Angiostatin treatment of immunized mice further enhanced the antitumor effect of tumor vaccination. CONCLUSION: Antitumor immune response could complement the therapeutic efficacy of angiostatin.     

肿瘤浸润性T细胞的代谢调控及干预策略研究进展

T细胞参与并维持免疫应答、免疫自稳态过程,肿瘤浸润性T细胞的功能和状态与抗肿瘤免疫密切相关。在肿瘤微环境（TME）中,T细胞抗肿瘤作用的发挥受到多重限制：TME的物理屏障阻止T细胞浸润;肿瘤细胞为满足其迅速增殖的需求使用有氧糖酵解的方式消耗大量葡萄糖,限制效应T细胞的功能;抑制性免疫细胞和肿瘤细胞的代谢产物大量堆积,改造TME,TME缺氧、营养匮乏、酸化、代谢物大量堆积,影响T细胞的正常代谢,损害其抗肿瘤能力。通过对肿瘤浸润性T细胞代谢的研究,以及靶向TME代谢的治疗策略进行综述,希望能为肿瘤免疫治疗提供新思路。     

Checkpoint-modulating immunotherapies in tumor treatment: Targets,drugs, and mechanisms

Tumor immunotherapy, as a new treatment of cancer, has been developing on the basis of tumor immunology. Tumor immunotherapy stimulates and enhances the function of immune system in human bodies, in order to control and kill tumor cells. It is often used as an adjuvant therapy combined with surgery, chemotherapy, radiotherapy and other conventional methods. Cancer immunotherapies involve cells, antibodies and cytokines, etc. Some immunotherapies are widely used to activate the immune system, while some others precisely target at different tumor antigens. With the development of tumor immunotherapy, immune regulation activities of small molecules and biological agents have been gradually becoming a hot research area these years. In this review, we summarize the therapeutic targets, drugs, biologics, and their mechanisms in tumor immunotherapies.     

Combining cytotoxic and immune-mediated gene therapy to treat brain tumors

Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as 'immune privileged', brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another important aspect of implementing gene therapy in the clinical arena is to be able to image the targeting of the therapeutics to the tumors, treatment effectiveness and progression of disease. We have therefore reviewed the most exciting non-invasive, in vivo imaging techniques which can be used in combination with gene therapy to monitor therapeutic efficacy over time.     

Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment (TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a light-controllable charge-reversal nanoparticle (LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer (TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC     

Present and future of lung cancer vaccines

New approaches are needed to improve the current treatment of lung cancer. Inducing an immune response against lung tumour cells with vaccines represents an attractive therapy. However, lung tumours had not been considered good targets for vaccine therapy and, therefore, immune approaches have not been studied extensively in this setting. Current experimental strategies for antitumour vaccines include the generation of active immune responses against specific tumour antigens. Understanding the mechanisms of antitumour immunity and identifying relevant tumour-specific antigens will probably improve therapeutic strategies and provide avenues for the future of lung cancer therapy. There have been a number of preclinical immunotherapy trials suggesting activity, and a smaller number of human clinical trials using various vaccines in lung cancer. Initial data from these trials have shown preliminary evidence of induction of immune responses and suggest clinical activity. This paper reviews some of the most important developments in vaccines for lung cancer.     

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core?shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.     

肿瘤免疫治疗中过继性细胞疗法的研究进展

肿瘤免疫疗法旨在利用免疫系统建立针对性的抗肿瘤免疫反应,激活肿瘤免疫细胞是免疫疗法的关键点。过继性细胞疗法是通过体外改造、扩增免疫细胞提高免疫功能,再回输患者体内以发挥抗肿瘤效应。除了已广泛应用于临床的嵌合抗原受体T细胞疗法,近年来T细胞受体-T细胞疗法、肿瘤浸润淋巴细胞疗法、嵌合抗原受体-自然杀伤细胞疗法、嵌合抗原受体-巨噬细胞疗法等新型过继性细胞疗法也开始进入临床。综述近年来过继性细胞疗法的研究进展,以期为基于该疗法进行肿瘤的免疫治疗提供参考。     

IL-18 immunoadjuvanted xenogeneic canine MMP-7 DNA vaccine overcomes immune tolerance and supresses the growth of murine mammary tumor

The development of the tumorigenesis and angiogenesis through proteolytic cleavage of extracellular matrix protein and basement membranes is promoted by Matrix metelloproteinases-7 (MMP-7). Consequently, MMP-7 is presumed as potential target for mammary cancer immunotherapy. However, MMP-7 is an endogenous tumor associated antigen (TAA); therefore, immunization is challenging. In current study, a potent anti-tumor immune response has been elicited through recombinant bivalent plasmid pVIVO2.IL18.cMMP7 which subside the highly metastatic 4 T1 cell line induced mammary tumors and efficiently negate the existing challenge of using MMP-7 as immunotherapeutic target. Balb/c mice were immunized with canine MMP-7 (cMMP-7) using interleukine-18 (IL-18), as an immunoadjuvant, to explore the potential of the combination regarding elicitation of a potent anti-tumor immune response. Mice vaccinated with pVIVO2.IL18.cMMP7 DNA plasmid reduced the tumor growth significantly along with augmentation of the immune response to fight against tumor antigen as depicted by substantial enrichment of CD4⁺ and CD8⁺ population in splenocytes, infiltration of immune system cells in tumor tissue and enhanced survival time of mice. Further, splenocyte supernatant examination of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were remarkably up-regulated demonstrating the stimulation of cell-mediated immune response. Thus the current observations vividly portray that administration of xenogeneic MMP-7 DNA vaccine bypasses the tolerance barrier.     

Anti-PD-L1 mediating tumor-targeted codelivery of liposomal irinotecan/JQ1 for chemo-immunotherapy

Immune checkpoint blockade therapy has become a first-line treatment in various cancers. But there are only a small percent of colorectal patients responding to PD-1/PD-L1 blockage immunotherapy. How to increase their treatment efficacy is an urgent and clinically unmet need. It is acknowledged that immunogenic cell death (ICD) induced by some specific chemotherapy can enhance antitumor immunity. Chemo-based combination therapy can yield improved outcomes by activating the immune system to eliminate the tumor, compared with monotherapy. Here, we develop a PD-L1-targeting immune liposome (P-Lipo) for co-delivering irinotecan (IRI) and JQ1, and this system can successfully elicit antitumor immunity in colorectal cancer through inducing ICD by IRI and interfering in the immunosuppressive PD-1/PD-L1 pathway by JQ1. P-Lipo increases intratumoral drug accumulation and promotes DC maturation, and thereby facilitates adaptive immune responses against tumor growth. The remodeling tumor immune microenvironment was reflected by the increased amount of CD8⁺ T cells and the release of IFN-γ, and the reduced CD4⁺Foxp3⁺ regulatory T cells (Tregs). Collectively, the P-Lipo codelivery system provides a chemo-immunotherapy strategy that can effectively remodel the tumor immune microenvironment and activate the host immune system and arrest tumor growth.     

程序性死亡受体1的检测方法及其在乳腺癌中表达的研究进展

近年来,肿瘤的免疫治疗已成为继传统手术、放疗、化疗、内分泌治疗和靶向药物治疗手段之后新的治疗方法,尤其以程序性死亡受体1(PD-1)/程序性死亡配体1(PD-L1)位靶点的免疫检查点抑制治疗使得非小细胞肺癌、黑色素瘤等恶性实体肿瘤患者获得了有效持久的临床获益。PD-L1的检测是免疫检查点抑制剂治疗的关键环节,但在乳腺癌中的其检测方法和判定标准尚未统一。就PD-L1的检测方法以及其在乳腺癌各分子分型中的表达进行综述。     

Immunotherapy of malignant gliomas using autologous and allogeneic tissue cells

Immunotherapy of brain tumors is rapidly emerging as a potential clinical option [1-3]. The quality and magnitude of immune responses evoked by the new generation anti-tumor vaccines is in general highly dependent on the source or choice of peptide antigens, and as well, a suitable immunopotentiator. Poorly immunogenic antigens, such as those present in tumor cell lysates, may not reliably provide stimulation like recombinant or DNA-encoded protein antigens might be expected to. In addition, the efficacy of the vaccine may depend on inherent counteracting measures of the tumor which dampen immune surveillance and immune effector activity triggered by immunization [4]. Our body has many means of limiting an immune response to our own (self) proteins. In particular, patients with gliomas exhibit a broad suppression of cell-mediated immunity [5-8]. Unfortunately, for most tumor vaccines the induction of local or systemic immune effector cells does not necessarily translate into objective clinical responses or increased survival [9]. Here we review immunotherapeutic approaches against gliomas and recent pre-clinical and clinical initiatives based on cellular or active immunization of the patient's immune system using autologous and allogeneic tissues or cultured cells. Available evidence shows that single modality cancer therapies likely remain suboptimal. Combination regimens targeting the immune system at multiple coordinated levels must be developed, and possibly combined with strategies to inhibit immune suppressive factors if significant clinical benefit is to be achieved.     

免疫检查点抑制剂治疗期间并发肺孢子菌感染：两例病例报道并文献复习

近年来,免疫检查点抑制剂（ICI）在临床中广泛应用,给肿瘤患者带来了比放疗、化疗更进一步的生存获益。然而,在免疫抑制剂增强细胞免疫抗肿瘤的同时,也有可能增强机体正常的免疫反应,导致机体免疫耐受紊乱,引起相应器官出现不适症状,称之为免疫相关不良反应。其中,免疫相关性肺炎往往较难诊断,严重者可致命。肺孢子菌肺炎（PCP）作为一种机会性真菌感染性疾病,常发生于免疫力低下人群。鉴于ICIs对免疫功能的促进作用,目前的主要观点认为,肿瘤免疫治疗并不会增加肺孢子菌感染的机会。本文报道了两例免疫治疗期间发生肺孢子菌感染的病例,以期进一步加深人们对免疫相关性肺炎及PCP的认识。     

姜黄素的免疫调节作用及其肿瘤免疫治疗的研究进展

癌症发病率逐年增长,且死亡率居高不下。肿瘤免疫治疗作为目前肿瘤治疗领域中最具前景的研究方向之一,其治疗手段主要包括过继性细胞治疗、免疫调节治疗、肿瘤疫苗治疗、分子靶向治疗等。姜黄素是姜黄中主要活性成分,主要通过抑制细胞增殖、诱导细胞凋亡、抑制肿瘤侵袭等机制发挥抗肿瘤功效。在免疫治疗领域,姜黄素通过调节机体的固有免疫系统、获得性免疫系统以及肿瘤相关分子的表达和活性达到抗肿瘤作用,并联合免疫检查点抑制剂、其他肿瘤免疫治疗方法用于肿瘤治疗。总结了姜黄素的免疫调节作用及其用于肿瘤免疫治疗的研究进展。     

Selective activation of intracellular signalling pathways in dendritic cells for cancer immunotherapy

One of the major challenges in achieving effective anti-cancer immunotherapy is to counteract immunological tolerance. Most tumor-associated antigens (TAAs) are sensed as self. Hence, naturally occurring tolerance towards them has to be overcome. Fortunately, there is increasing evidence that anti-tumor immune responses occur and play a crucial role in the success of well-established anti-neoplastic therapies such as radiotherapy and chemotherapy. In fact, their effectiveness relies on signalling by pattern recognition receptors such as Toll-like receptors (TLRs). TLR signal transduction involves activation of a few well-known pathways, of which nuclear factor κB (NF-κB) and mitogen activated protein kinases (MAPKs) are possibly the best characterized. Therefore, constitutive activation of these pathways in immune cells can potentially enhance anti-tumor immunity, especially when targeted to professional antigen presenting cells (APCs) such as dendritic cells (DCs). Several strategies have been devised to test this hypothesis, including constitutive activation of TLRs, NF-κB and MAPKs (extracellular-signal regulated kinase (ERK), p38 and c-Jun kinase 1 (JNK1)). Activation of these pathways in mouse and human DCs has differential effects in immunogenicity and in many cases, enhanced antitumor immunity in pre-clinical models, establishing the basis for future clinical applications.     

肿瘤免疫治疗新靶标PGE2受体EP4的研究进展

肿瘤免疫治疗已成为人们对抗癌症的重要手段,但响应率低仍是目前亟需解决的关键问题。大量研究表明,逆转肿瘤免疫抑制是阻断肿瘤免疫逃逸、增强和扩大免疫疗法疗效的重要策略。前列腺素E₂(PGE₂)是肿瘤微环境中的强效免疫介质,可特异性结合细胞膜上的七次跨膜蛋白EP4受体,诱导肿瘤微环境免疫抑制,驱动肿瘤免疫逃逸。特异性阻断PGE₂/EP4信号通路可有效解除肿瘤微环境免疫抑制,增强抗肿瘤免疫反应,促进肿瘤消退。本文从EP4受体的结构、信号转导、调控机制及其拮抗剂开发现状等方面阐述了EP4受体在肿瘤免疫治疗领域的新进展和新发现,并展望了新的发展方向。     

Combining immune checkpoint blockade with ATP-based immunogenic cell death amplifier for cancer chemo-immunotherapyOA

Amplifying eat me signal during tumor immunogenic cell death(ICD) cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary "eat me signal" for ICD),a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy.Doxorubicin(DOX),ATP and ferrous ions(Fe²⁺) were co-assembled into nanosized amplifier(ADO-Fe) through π-π stacking and coordination effect.Meanwhile,phenylboric acid-polyethylene glycol-phenylbor...