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。     

Light-responsive nanomedicine for cancer immunotherapy

Immunotherapy emerged as a paradigm shift in cancer treatments, which can effectively inhibit cancer progression by activating the immune system. Remarkable clinical outcomes have been achieved through recent advances in cancer immunotherapy, including checkpoint blockades, adoptive cellular therapy, cancer vaccine, and tumor microenvironment modulation. However, extending the application of immunotherapy in cancer patients has been limited by the low response rate and side effects such as autoimmune toxicities. With great progress being made in nanotechnology, nanomedicine has been exploited to overcome biological barriers for drug delivery. Given the spatiotemporal control, light-responsive nanomedicine is of great interest in designing precise modality for cancer immunotherapy. Herein, we summarized current research utilizing light-responsive nanoplatforms to enhance checkpoint blockade immunotherapy, facilitate targeted delivery of cancer vaccines, activate immune cell functions, and modulate tumor microenvironment. The clinical translation potential of those designs is highlighted and challenges for the next breakthrough in cancer immunotherapy are discussed.     

A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.     

Abscopal effect in radioimmunotherapy

Abscopal effect is an interesting phenomenon in radiobiology that causes activation of immune system against cancer cells. Traditionally, this phenomenon was known as a suppressor of non-irradiated tumors or metastasis. However, it can be used as a stimulator of the immune system against primary tumor during radiotherapy. Immunotherapy, a novel tumor therapy modality, also triggers immune system against cancer. To date, some immunotherapy types have been developed. However, immune checkpoint blockade is a more common modality and some drugs have been approved by the FDA. Studies have shown that radiotherapy or immunotherapy administered alone have low efficiency for tumor control. However, their combination has a more potent anti-tumor immunity. For this aim, it is important to induce abscopal effect in primary tumors, and also use appropriate drugs to target the mechanisms involved in the exhaustion of cytotoxic CD8+T lymphocytes (CTLs) and natural killer (NK) cells. Among the different radiotherapy techniques, stereotactic body radiation therapy (SBRT) with some few fractionations is the best choice for inducing abscopal effect. On the other hand, programmed cell death 1 (PD-1) is known as one of the best targets for triggering anti-tumor immunity. This combination is known as the best choice among various strategies for radioimmunotherapy. However, there is the need for other strategies to improve the duration of immune system’s activity within tumor microenvironment (TME). In this review, we explain the cellular and molecular mechanisms behind abscopal effect by radiotherapy and evaluate the molecular targets which induce potent anti-tumor immunity.     

进展期大肠癌免疫疗法的研究进展

目前,进展期大肠癌治疗缺乏有效手段,亟待研发新的治疗技术。近年来,免疫疗法已在血液系统肿瘤和黑素瘤的治疗中显示有显著疗效,且有多项免疫治疗技术试用于大肠癌治疗,包括肿瘤治疗性疫苗、免疫检查点抑制剂和过继细胞疗法等。其中,免疫检查点抑制剂抗程序性细胞死亡受体-1抗体已在DNA错配修复缺陷型大肠癌的治疗中显示有很好的疗效,但在血液系统肿瘤治疗中显示有显著疗效的嵌合抗原受体修饰的T细胞疗法却在大肠癌等实体瘤治疗中显示疗效欠佳,有一系列的问题需予解决。不过,免疫疗法已成为继手术、放疗和化疗后的第四大肿瘤疗法,将为进展期大肠癌治疗带来新的希望。     

Autophagy-related gene expression classification defines three molecular subtypes with distinct clinical and microenvironment cell infiltration characteristics in colon cancer

BackgroundMultiple molecular subtypes with distinct clinical outcomes in colon cancer have been identified in recent years. Nonetheless, the autophagy-related molecular subtypes as well as its mediated tumor microenvironment (TME) cell infiltration characteristics have not been fully understood.MethodsBased on the seven colon cancer cohorts with 1580 samples, we performed a comprehensive genomic analysis to explore the molecular subtypes mediated by autophagy-related genes. The single-sample gene-set enrichment analysis (ssGSEA) was used to quantify the relative abundance of each cell infiltration in the TME. Unsupervised methods were used to perform autophagy subtype clustering. Least absolute shrinkage and selection operator regression (LASSO) was used to construct autophagy characterization score (APCS) signature.ResultsWe determined three distinct autophagy-related molecular subtypes in colon cancer. The three autophagy subtypes presented significant survival differences. Microenvironment analyses revealed the heterogeneous TME immune cell infiltration characterization between three subtypes. Cluster 1 autophagy subtype was characterized by abundant innate and adaptive immune cell infiltration. This subtype exhibited an enhanced stromal activity including activated pathways of epithelial-mesenchymal transition, TGF-β and angiogenesis, and an increased infiltration of fibroblasts and endothelial cells. The expression of immune checkpoint molecules was also significantly up-regulated, which may mediate immune escape in Cluster 1 subtype. Cluster 2 subtype was characterized by relatively lower TME immune cell infiltration and enhanced DNA damage repair pathways. Cluster 3 subtype was characterized by the suppression of immunity. Patients with high APCS, with poorer survival, presented a significantly positive correlation with TME stromal activity. Low APCS, relevant to activated damage repair pathways, showed enhanced responses to anti-PD-1/PD-L1 immunotherapy. Two immunotherapy cohorts confirmed patients with low APCS exhibited prominently enhanced clinical response and treatment advantages.ConclusionsThis study may help understand the molecular characterization of autophagy-related subtypes. We demonstrated the autophagy genes in colon cancer could drive the heterogeneity of TME immune cell infiltration. Our study represented a step toward personalized immunotherapy in colon cancer.     

Nanomedicines modulating tumor immunosuppressive cells to enhance cancer immunotherapy

Cancer immunotherapy has veered the paradigm of cancer treatment. Despite recent advances in immunotherapy for improved antitumor efficacy, the complicated tumor microenvironment (TME) is highly immunosuppressive, yielding both astounding and unsatisfactory clinical successes. In this regard, clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME. Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME. The immunosuppressive TME may even dampen the efficacy of antitumor immunity. Recently, some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment (TIME) for robust immunotherapeutic responses. In this review, we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy, especially those unique classes associated with the immunosuppressive effect. The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation. After introducing the various strategies, we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.     

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies, on account of its good safety and long-term memory ability. Discouragingly, low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside. However, it has become evident that, although the immunosuppressive tumor microenvironment (TME) plays a pivotal role in facilitating tumor progression and metastasis, it also provides various potential targets for remodeling the immunosuppressive TME, which can consequently bolster the effectiveness of antitumor response and tumor suppression. Additionally, the particular characteristics of TME, in turn, can be exploited as avenues for designing diverse precise targeting nanomedicines. In general, it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME, thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy. Herein, we will illustrate several formation mechanisms of immunosuppressive TME. More importantly, a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients' immune systems, will be reviewed. Ultimately, we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy. Hopefully, the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.     

Programming the immune checkpoint to treat hematologic malignancies

Introduction: Hematologic malignancies manipulate the immune suppressive pathways involving CTLA-4, PD-1, and others to promote immune tolerance of cancer. New monoclonal antibodies targeting immune checkpoints are showing meaningful responses in the treatment of relapsed and refractory Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. The basis for success of anti-PD-1 therapy appears to be expression of PD-L1 on tumor cells and cells of the tumor microenvironment (TME). While adverse events associated with immune checkpoint inhibitors are capable of generating auto-immune phenomena, in general these therapies are well tolerated.

Areas covered: In this review, the authors discuss the development of immune checkpoint inhibitors and activators which hold promise as useful therapies in malignancies of hematologic origin, since many exploit endogenous pathways to induce tolerance. By programming the immune response to attack hematologic malignancies, unique regimens can be developed to optimally treat patients with curative potential.

Expert opinion: The utilization of immune checkpoint targeting agents to boost the innate and acquired immune systems to eradicate human malignancies represents a unique opportunity to develop novel therapies with increased clinical efficacy. Side effects of these therapies come with the price of auto-immune phenomena that require appropriate management.     

Cell membrane coated-nanoparticles for cancer immunotherapy

Cancer immunotherapy can effectively inhibit cancer progression by activating the autoimmune system, with low toxicity and high effectiveness. Some of cancer immunotherapy had positive effects on clinical cancer treatment. However, cancer immunotherapy is still restricted by cancer heterogeneity, immune cell disability, tumor immunosuppressive microenvironment and systemic immune toxicity. Cell membrane-coated nanoparticles (CMCNs) inherit abundant source cell-relevant functions, including “self” markers, cross-talking with the immune system, biological targeting, and homing to specific regions. These enable them to possess preferred characteristics, including better biological compatibility, weak immunogenicity, immune escaping, a prolonged circulation, and tumor targeting. Therefore, they are applied to precisely deliver drugs and promote the effect of cancer immunotherapy. In the review, we summarize the latest researches of biomimetic CMCNs for cancer immunotherapy, outline the existing specific cancer immune therapies, explore the unique functions and molecular mechanisms of various cell membrane-coated nanoparticles, and analyze the challenges which CMCNs face in clinical translation.     

肿瘤免疫检查点PD-1/PD-L1抑制剂的中药活性成分研究进展

肿瘤免疫治疗已成为新型的癌症治疗手段,有望彻底消除肿瘤。免疫检查点抑制剂,特别是程序性死亡受体-1（PD-1）和程序性死亡受体-配体1（PD-L1）抗体在多种实体瘤的治疗中取得很好的临床疗效,但是生物制剂存在免疫原性强、价格昂贵等缺点,因此,寻找免疫检查点小分子抑制剂成为未来肿瘤免疫疗法的新挑战。本文将综述近年发现的抑制PD-1/PD-L1表达的中药活性小分子及其对肿瘤免疫微环境的调控作用。     

Strategies to overcome obstacles to successful immunotherapy of melanoma

The immunogenicity of malignant melanomas has been recognized by the observed recruitment of tumor-specific cytotoxic T-cells (CTL), leading to the identification of several melanoma associated antigen (MAA). However, numerous strategies to treat melanoma with immunotherapy have resulted in only partial success. In this editorial, we discuss recent data related to the ability of tumors to elude immune responses. We therefore discuss different strategies to induce a clinically effective immune response. These approaches include 1) immunostimulation: including peptide/protein based vaccines, dendritic cell vaccines, and adoptive cell transfer; and 2) overcoming immunosuppression, including targeting of checkpoint molecules such as CTLA-4, circumventing the activity of Tregs, and assuring antigen expression by tumor cells (thwarting antigen silencing). Finally, we discuss recent advances in gene therapy, including adoptive therapy with engineered T cell receptors (TCRs). These issues lead to the conclusion that successful immunotherapy in malignant melanoma requires a combination of strategies aimed at both inducing immunostimulation and blocking immunosuppression.     

Comprehensive analysis of CTLA-4 in the tumor immune microenvironment of 33 cancer types

Immunotherapy has recently become a powerful weapon against cancer. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) was the first immune checkpoint used for immunotherapy. However, CTLA-4-related mechanisms in various cancers have not been comprehensively investigated. This aim of this study was an in-depth investigation of CTLA-4 in the tumor microenvironment and its relationship with other immunomodulators, immune-related pathways and survival outcomes of 33 cancer types.Overall 9,743 tumor samples and 710 normal samples of 33 cancer types from The Cancer Genome Atlas (TCGA) database were included. CTLA-4 expression level was compared between tumor and normal tissues in 22 cancer types. The microenvironment cell populations (MCP)-counter method was used to analyze the correlation between CTLA-4 and immune cell infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed to investigate its relationship with immune pathways. Survival analysis was conducted using the Kaplan-Meier method with log-rank test.CTLA-4 expression was found to be increased in some types of cancer and decreased in other cancer types (P < 0.05). When comparing between different tumor tissues, CTLA-4 was lowest in uveal melanoma (UVM). MCP analysis demonstrated that CTLA-4 had a strong correlation with T cells in almost all cancer types and that CTLA-4 showed a positive correlation with most immune cells in UVM. Immune pathway analysis found that CTLA-4 is involved in a variety of immune pathways. Survival analysis revealed that CTLA-4 can predict patients’ survival outcomes. This comprehensive analysis of CTLA-4 will promote anti-CTLA-4 therapy and personalized combined immunotherapy.     

Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy

Abstract

Cancer immunotherapy has been increasingly utilised to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionising the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity and, therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced. Small-molecule inhibitors could offer inherent advantages in terms of pharmacokinetics and druggability, thereby providing additional methods for cancer treatment and achieving better therapeutic effects. In this review, we first discuss how PD-1/PD-L1-targeting inhibitors modulate the relationship between immune cells and tumour cells in tumour immunotherapy. Second, we discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with immunotherapy and targeted therapy. Third, this review is the first to summarise the current clinical and preclinical evidence regarding small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint, considering features and responses related to the tumours and to the host immune system.

Trial registration: ClinicalTrials.gov identifier: NCT02812875.     

Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.     

Immune cell membrane-based biomimetic nanomedicine for treating cancer metastasis

Metastasis is the leading cause of cancer-related death. Despite extensive treatment, the prognosis for patients with metastatic cancer remains poor. In addition to conventional surgical resection,radiotherapy, immunotherapy, chemotherapy, and targeted therapy, various nanobiomaterials have attracted attention for their enhanced antitumor performance and low off-target effects. However, nanomedicines exhibit certain limitations in clinical applications, such as rapid clearance from the body, low...     

Emerging immunotherapies for glioblastoma

Introduction: Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA’s approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM.

Areas covered: Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy.

Expert opinion: Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.     

IL-4Rα aptamer-liposome-CpG oligodeoxynucleotides suppress tumour growth by targeting the tumour microenvironment

Tumour immunosuppressive microenvironments inhibit antigen-specific cellular responses and interfere with CpG-mediated immunotherapy. Overcoming tumour microenvironment (TME) immunosuppression is an important strategy for effective therapy. This study investigated the ability of a tumour-targeting IL-4Rα aptamer-liposome-CpG ODN delivery system to introduce CpG into tumours and overcome the immunosuppressive TME. The IL-4Rα-liposome-CpG delivery system was prepared. FAM-CpG visualisation was used to demonstrate tumour targeting in vitro and in vivo. Anti-tumour effects of this delivery system were evaluated in CT26 tumour-bearing mice. Mechanisms for conquering the TME were investigated. FAM-CpG was better distributed into the tumours upon treatment with IL-4Rα-liposome-FAM-CpG compared to distribution in the control group in vitro and in vivo. IL-4Rα-aptamer-liposome-CpG treatment inhibited distinct myeloid-derived suppressor cell populations in tumours and bone marrow. Similar profiles were observed for regulatory T cells in tumours. In CT26 tumour-bearing mice, IL-4Rα-liposome-CpG treatment exhibited enhanced anti-tumour activity. Increased mRNA levels of TNF-α, IL-2, and IL-12, and decreased mRNA levels of VEGF, IL-6, IL-10, MMP9, arginase-1, inducible NOS, CXCL9, p-Stat3, and NF-κB were observed in tumours upon IL-4R-liposome-CpG-treatment. The results suggested that pharmacologic targeting by the IL-4R aptamer-liposome-CpG system improves TME therapeutic benefit and provides a rationale for cancer immunotherapies.     

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     

肝细胞癌的血管正常化与免疫治疗 #br#

肝细胞癌（HCC）是常见的恶性肿瘤之一,大部分患者确诊时往往为晚期,失去手术的机会,此时药物治疗 成为重要的治疗手段,包括化疗、靶向、免疫、中药及内分泌治疗等。免疫治疗是一种新兴的癌症治疗方式,然而异 常的肿瘤血管形成免疫抑制的肿瘤微环境,限制了免疫治疗的发展。抗血管生成治疗能够抑制肿瘤血管生长,修复 异常的肿瘤血管系统,成为改善免疫治疗的新策略。本文就HCC的血管正常化与免疫治疗的关系及两者的联合治 疗进行综述。