T细胞免疫球蛋白黏蛋白3在结直肠癌中的研究进展

T细胞免疫球蛋白黏蛋白3（T-cell immunoglobulin mucin 3,TIM-3）是近年来被广泛研究的免疫调节蛋白,它在肿瘤的免疫治疗中具有重要的意义。TIM-3是属于TIM家族的I型跨膜蛋白,其在多种免疫细胞和非免疫细胞中均有表达。TIM-3在机体免疫反应过程中起到负调节的作用,TIM-3与配体相互作用后可诱导T细胞凋亡,从而能够抑制免疫细胞的活性,使肿瘤细胞能够逃避免疫系统的攻击。TIM-3已成为了肿瘤免疫治疗的一个关键靶点,联合阻断TIM-3和其他免疫检查点分子,可以增强T细胞的杀伤能力,进一步提高抗癌治疗的效果。本文就TIM-3与结直肠癌的发生发展、临床病理特征、预后及免疫治疗等的相关研究作一综述,探讨TIM-3作为结直肠癌免疫治疗靶点的重要地位及其临床价值。     

T淋巴细胞免疫球蛋白黏蛋白-3在肿瘤免疫中的研究进展北大核心CSCD

恶性肿瘤发病率逐年升高,对人类健康造成严重影响,目前非手术治疗手段主要有放疗、化疗和分子靶向治疗。在机体抗肿瘤效应中,T淋巴细胞介导的细胞免疫起到了关键作用。在免疫应答过程中,需要协同刺激信号的参与才能激活T淋巴细胞,而这些信号需要经过"免疫检查点"进行调控。T淋巴细胞免疫球蛋白黏蛋白基因家族TIM-3作为一种负性调节分子选择性地在活化的Thl细胞表面表达,并在多种肿瘤的发生发展中起到重要调节作用。本文将从TIM-3结构、TIM-3配体、TIM-3在肿瘤的表达及其免疫调节机制和TIM-3的免疫治疗方面,对TIM-3在肿瘤免疫研究领域的最新进展进行综述。     

TIM-3分子与肿瘤免疫抑制

T细胞免疫球蛋白黏蛋白3（T-cell immunoglobulin mucin 3,TIM-3）是免疫检查点分子之一,表达于多种免疫细 胞及肿瘤细胞。在肿瘤微环境（tumor microenvironment,TME）中,TIM-3 与含其主要配体 Gal-9 的 T 细胞等相互作用, 介导细胞凋亡而参与肿瘤的免疫抑制及其发生发展。抗 TIM-3 抗体抗肿瘤治疗目前处于临床前研究阶段,它可能成为肿 瘤治疗的明星分子。     

免疫检查点分子联合CAR-T细胞治疗实体肿瘤研究进展

免疫检查点分子是一组表达于免疫细胞表面,主要调控免疫细胞稳态的分子。嵌合抗原受体修饰的T细胞（CAR-T免疫疗法是通过生物技术构建表达特异性抗原的人工合成T细胞,实现肿瘤靶向杀伤的免疫治疗技术。CAR-T治疗策略已在血液肿瘤临床治疗中取得了较好的疗效,但针对实体肿瘤的CAR-T免疫治疗技术有待进一步研究完善。本文就免疫检查点分子联用CAR-T免疫疗法在实体肿瘤治疗中面临的问题及新进展进行综述。     

以NKG2A 为靶点的肿瘤免疫治疗：现状、问题与对策

自然杀伤细胞2 族成员A（NKG2A）为免疫细胞表面重要的免疫检查点,NKG2A 与其配体HLA-E 的结合会抑制NK 细胞和T 细胞的免疫效应功能,甚至使之发生功能耗竭,导致肿瘤细胞免疫逃逸。抗NKG2A 抗体可以通过阻断NKG2A 与其配 体的结合而恢复NK 细胞和T 细胞的功能,从而唤醒强大的抗肿瘤免疫。与其他免疫检查点（如PD-1、CTLA-4 等）相比,NKG2A 阻断性抗体在临床肿瘤治疗中具有其独特的优势,其阻断NKG2A 的识别及其信号通路,能够同时逆转T 细胞和NK 细胞的功能 耗竭,全面唤醒机体的抗肿瘤效应。基于NKG2A 的抗肿瘤免疫疗法正在开展多项临床试验,显示出良好的安全性和有效性。本 文就NKG2A 及其配体的表达与信号转导、NKG2A 介导免疫细胞的功能耗竭,以及目前以NKG2A 为靶点的肿瘤免疫治疗策略和 临床研究进展现状、存在问题和对策进行阐述,为以NKG2A 为靶点的肿瘤免疫治疗策略的开发和临床应用提供参考。     

治疗非小细胞肺癌新药纳武单抗的研发和临床转化

[摘要] 纳武单抗（nivolumab）为一全人源化IgG4 单克隆抗体靶向PD-1 免疫检查点抑制剂,主要通过克服患者体内的免疫抑制,重新激活免疫细胞来杀伤肿瘤细胞,是一种全新的抗肿瘤理念。纳武单抗作为抗PD-1 受体免疫检查点抑制剂,可通过封闭T 淋巴细胞的PD-1,阻断其与肿瘤细胞表面PD-L1 结合,解除肿瘤细胞对免疫细胞的抑制,使免疫细胞重新发挥抗肿瘤免疫作用而杀伤肿瘤细胞。纳武单抗于2015 年3 月被美国FDA 批准治疗铂基治疗进展后转移性鳞状非小细胞肺癌（NSCLC）。7 个月后,FDA在同样条件下批准该药物用于非鳞状NSCLC患者。本文主要介绍纳武单抗的药物作用机制、药效学、药动学、临床试验和安全性等的最新研究进展,为临床用药提供参考。     

PD-L1 表达及其调控在胶质瘤免疫治疗中作用的研究进展

以PD-1/PD-L1 轴为靶点的免疫检查点阻断治疗策略已经应用于临床上多种肿瘤的治疗。PD-L1 作为表达于肿瘤细胞中的重要免疫调控靶点,可以应用单克隆抗体阻断其介导的免疫抑制作用,从而恢复T细胞对肿瘤细胞的识别和杀伤。但是,PD-L1 的表达受多种因素调控,包括基因组水平、翻译后修饰过程以及翻译后CMTM4/6 介导的内含体循环调控等。本文就PD-L1 蛋白表达的受调控过程及其在胶质瘤免疫治疗中作用的研究进展作一综述。     

免疫检查点在肿瘤微环境中对DC成熟和功能调控的研究进展

[摘要] 树突状细胞（DC）是体内功能强大的抗原提呈细胞（APC）,在机体抗肿瘤免疫反应的过程中起着关键的作用。成熟DC具有激活T淋巴细胞并激活抗肿瘤免疫反应的功能,以DC为基础的抗肿瘤免疫疗法显示出良好的应用前景。免疫检查点疗法是肿瘤免疫治疗的另一强有力手段,以PD-1 和CTLA-4 为代表的免疫检查点分子在肿瘤微环境中起着免疫调节的作用,同时也对DC的成熟和功能起着重要的调控作用。肿瘤微环境中的未成熟DC和免疫检查点分子是肿瘤免疫逃逸的重要因素。因此探究免疫检查点分子对DC成熟及功能的调控机制对于抗肿瘤治疗的研究具有非常重要的意义。本文从DC的视角,阐述了肿瘤微环境中免疫检查点分子对DC成熟及功能的调控机制以及免疫检查点靶向药物联合DC疫苗应用于肿瘤临床实验的最新研究进展。     

T细胞免疫球蛋白黏蛋白分子-3 精细化调控免疫应答的机制

机体免疫应答的动态变化及空间差异是疾病精细化治疗的理论基础之一,同一免疫调节分子在不同时空条件下的功能可能截然不同。T细胞免疫球蛋白黏蛋白分子-3（T cell immunoglobulin and mucin-containing protein-3,TIM-3）是新近鉴定出的免疫检查点分子,与CTLA-4、PD-1 等一样参与了免疫细胞稳态调控,TIM-3 的异常高表达与肿瘤、慢性病毒感染的相关性使其成为免疫靶向治疗的关注点。靶向免疫检查点分子的临床治疗给患者带来了希望,但也存在效率不高、耐药乃至副作用明显等情况,问题的解决有赖于该类分子精细调控机制的阐明。大多数数据显示TIM-3 具免疫抑制作用,但也有相反的报道。TIM-3 的配体多样,胞内信号转导机制仍不十分明确。此外,血清中存在的可溶性TIM-3 蛋白的功能及临床意义目前尚不清楚。如果免疫系统进化的过程中也赋予了TIM-3 多重的免疫调节功能,阐明其调控机制必将对后续的应用研究提供重要参考。     

针对免疫检查点的乳腺癌治疗研究进展

通过免疫检查点分子和配体结合而激活的免疫检查点通路是活化免疫细胞的抑制性第二信号,维持机体自身免疫耐受,抑制免疫过度激活从而保护自身组织。其中主要包括CTLA-4/CD80、CD86,PD-1/PD-L1,A2aR/细胞外腺苷和Tim-3/半乳凝素-9 等。乳腺癌细胞通过高表达免疫检查点分子配体介导免疫逃逸,通过PI3K通路、JAK/STAT通路和NF-κB通路参与免疫作用机制。目前,针对免疫检查点的乳腺癌治疗策略包括直接阻断T细胞表面的免疫检查点分子,如单克隆抗体单一治疗、单克隆抗体间联合治疗、单克隆抗体联合化疗药物治疗、单克隆抗体联合物理疗法、基因靶向治疗等,以及间接阻断肿瘤细胞及其微环境的免疫检查点分子配体,其研究热点主要集中在PD-L1上,具体方法主要为单克隆抗体以及基因靶向治疗。     

Expression of the Immune Checkpoint Regulators LAG-3 and TIM-3 in Classical Hodgkin Lymphoma

IntroductionThe role of the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis is well established in classical Hodgkin lymphoma (HL), where PD-1 blockade demonstrated spectacular efficacy in relapsed/refractory disease. However, little is known about the frequency and cellular distribution of other immune checkpoints in HL samples.Patients and MethodsUsing immunohistochemistry, we investigated, along with PD-L1 and PD-1, the expression of lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) in 57 biopsy samples of patients with classical HL.ResultsHodgkin and Reed/Sternberg (HRS) cells were strongly positive for PD-L1 in nearly all cases. HRS cells were TIM-3 positive in 36% of samples, whereas LAG-3 was rarely expressed (5.2%). In the microenvironment, PD-1, LAG-3, and TIM-3 were expressed by ≥ 5% of cells in 65%, 98%, and 96% of cases, respectively. T-cell rosettes surrounding HRS cells consisted of CD4⁺ FoxP3? helper T cells expressing both PD-1 and LAG-3, with a variable expression of TIM-3.ConclusionThis study demonstrates for the first time that LAG-3 and TIM-3 are nearly always expressed in the microenvironment of classical HL. This may constitute the basis for targeting LAG-3 or TIM-3 in combination with anti–PD-1 antibodies in the treatment of relapsed/refractory HL.     

PD-1/PD-L1 blockade in cancer treatment: perspectives and issues

Recent studies showed that tumor cells ‘edit’ host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called “cancer immune escape.” One of the most important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment.     

Assays for predicting and monitoring responses to lung cancer immunotherapy

Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway.KEYWORDS : Immunotherapy, lung cancer, programmed cell death 1 (PD-1), PD-1 ligand (PD-L1), antibody     

Rationale for anti-OX40 cancer immunotherapy

Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade –based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials. Accumulating preclinical evidence supports their clinical development. However, conflicting results and controversies between in vitro and in vivo data point to the need for comprehensive ancillary studies to be performed in upcoming clinical trials to better understand the mechanism of action of anti-OX40 mAbs-based therapy.     

Basics of PD-1 in self-tolerance,infection, and cancer immunity

Successful cancer treatment requires understanding host immune response against tumor cells. PD-1 belongs to the CD28 superfamily of receptors that work as “checkpoints” of immune activation. PD-1 maintains immune self-tolerance to prevent autoimmunity and controls T-cell reaction during infection to prevent excessive tissue damage. Tumor cells that arise from normal tissue acquire mutations that can be targeted by lymphocytes. Accumulating lines of evidence suggest that tumor cells evade host immune attack by expressing physiological PD-1 ligands and stimulating PD-1 on the lymphocytes. Based on this idea, researchers have successfully demonstrated that systemic administration of monoclonal antibodies that inhibit the binding of PD-1 to the ligands reactivated T cells and augmented the anti-cancer immune response. In this review, I summarize the basics of T-cell biology and its regulation by PD-1 and discuss the current understanding and questions about this multifaceted molecule.     

Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity

Combination therapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4⁺ T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA-4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg-cell-mediated immunosuppressive functions, suppressing antigen-presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti-CTLA-4 mAb with antibody-dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that CTLA-4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg-cell proliferation in mouse models. CTLA-4 blockade also augmented CTLA-4-independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor-infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg-cell depletion to achieve tumor regression in response to CTLA-4 blockade therapies.     

Complement receptor C5aR1 blockade reprograms tumor-associated macrophages and synergizes with anti-PD-1 therapy in gastric cancer

In gastric cancer (GC), the therapeutic response of immune checkpoint blockade (ICB) remains suboptimal. Targeting myeloid cell checkpoints might be feasible as adjuvant to current ICB regimens. We sought to evaluate the crucial role of C5aR1⁺ TAMs in regulating antitumor immunity and the efficacy of combinatorial treatment with antiprogrammed cell death protein-1 (PD-1) and C5aR1 blockade. Here, we found that C5aR1 was predominantly expressed on macrophages and high level of C5aR1⁺ TAMs infiltration could predict poor prognosis and inferior chemotherapeutic response. The flow cytometry (FCM) and single-cell RNA-seq (scRNA-seq) data revealed that C5aR1⁺ TAMs exhibited immunosuppressive property which might contribute to CD8⁺ T cell dysfunction. Blockade of C5aR1 could diminish the immunosuppressive function of TAMs and led to reinvigorated CD8⁺ T cells mediated antitumor immunity. Moreover, using in vitro intervention experiment based on fresh GC surgical specimens, we discovered that C5aR1 blockade exert a synergistic effect when combined with PD-1 inhibitor for tumor clearance. Our study demonstrated that C5aR1 is a critical myeloid checkpoint and plays a crucial role in regulating the immunosuppressive property of TAMs and CD8⁺ T cell immune tolerance. C5aR1 blockade reprograms TAMs and reinvigorated the cytotoxicity of CD8⁺ T cells, thus improving the efficacy of anti-PD-1 therapy for tumor eradication in GC.     

Modulation of Immune System Inhibitory Checkpoints in Colorectal Cancer

T cell infiltration of colorectal cancer is associated with improved clinical outcome, underlining the importance of the immune system in cancer control; however, immune checkpoints, including the inhibitory T cell molecules CTLA-4 and PD-1 that temper the native immune response, mitigating autoimmunity, are coopted by tumors to facilitate escape from immune surveillance. Blockade of CTLA-4 and PD-1 and its ligand PD-L1, expressed by many tumors, have shown impressive activity in melanoma, renal cell carcinoma, and lung cancer. Immune checkpoint inhibition has been less well studied in colorectal cancer, but preclinical and clinical investigations are in progress.