Immune microenvironment profiles of tumor immune equilibrium and immune escape states of mouse sarcoma

Cancer immunoediting consists of three distinct phases: elimination, equilibrium and escape. Here, for the first time, we investigated the immune microenvironment profiles of tumor immune equilibrium and immune escape states in 3′-methylcholanthrene-induced murine sarcoma model. Our study indicates the relative balance of monocytic MDSCs and antitumor immunity cells (especially CTLs, NK cells and γδT cells) may involve in maintaining tumor cells in a state of immune-mediated dormancy. In addition, high percentages of Treg cells and PMN-MDSCs are associated with the tumor immune escape state – mice with progressing sarcomas. In summary, the relative balance of immune effector cells and suppressive populations in the tumor microenvironment may involve in determining the fate of tumors.     

恶性肿瘤患者血清中免疫球蛋白类型的剖析观察

目的：评价恶性肿瘤患者的免疫球蛋白反应类型。方法：将血清免疫球蛋白（Ｉｇ）剖解为游离和复合两部分进行研究。以食管癌、喉癌、胃癌、乳腺癌、子宫癌、鼻咽癌、卵巢癌和非霍奇金淋巴瘤（ＮＨＬ）与健康者分别为实验组和对照组。结果：患者游离Ｉｇ的变化与总Ｉｇ一致，而复合Ｉｇ则与之不同，对其的检测更有利于对患者免疫状况的评价。从而说明，既往有关血清Ｉｇ含量的测定，主要反映游离Ｉｇ部分的免疫反应状况。结论：免疫反应产物的剖解分析可以更进一步认识免疫反应本质。在对肿瘤患者Ｉｇ比例的研究中，发现肿瘤患者的复合ＩｇＧ普遍严重下降。从而认为特异性ＩｇＧ水平的明显下降是患者免疫功能降低的重要原因，并提出深入研究其机理，将可能为探索肿瘤发病机理和治疗找到一条新路     

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。     

免疫检查点在乳腺癌中的研究进展

免疫检查点对于维持自身免疫耐受、避免免疫系统对正常组织进行攻击发挥着至关重要的作用。肿瘤细胞能够利用免疫检查点通路的激活逃避免疫系统的识别。目前最重要的免疫检查点为细胞毒T淋巴细胞相关抗原-4（CTLA-4）、程序性死亡受体-1（PD-1）及程序性死亡受体配体-1（PD-L1）。肿瘤细胞PD-L1通过与活化的T细胞的PD-1结合,能够通过诱导T细胞的凋亡降低肿瘤免疫反应。免疫检查点抑制剂的应用能够延长肿瘤患者的生存时间。尽管目前对于免疫检查点认识有限,但免疫检查点抑制剂作为新的治疗方法有望改变乳腺癌的治疗模式。本篇综述将介绍乳腺癌中免疫检查点的研究进展。     

miRNA调节免疫检查点在肿瘤治疗中的研究进展

肿瘤发生和发展的主要机制之一是免疫反应对癌症特异性抗原的沉默,癌症免疫监视的缺陷可能发生在肿瘤进展的任何阶段。肿瘤微环境中,对T淋巴细胞有活化或抑制作用的免疫检查点分子的异常表达可引起肿瘤细胞的免疫耐受或逃逸。靶向免疫检查点分子(如PD-1及其配体PD-L1等)已被证实是治疗多种类型癌症的新方向。微小RNA(miRNAs)在肿瘤微环境中有重要作用,研究表明一些肿瘤中miRNA的表达特异性高,其对免疫应答特别是早期调节有非常重要的作用。因此,miRNA可能成为癌症治疗中调节免疫检查点的理想分子。多种miRNA在癌细胞中异常表达,为癌症治疗提供了新的机遇,但这些miRNA的确切功能及其与免疫检查点分子间的相互作用还在探索阶段。本综述总结了近来关于miRNA作为免疫检查点分子调节剂的研究结果及其在临床实践中治疗癌症的潜在应用。     

免疫检查点抑制剂在小细胞肺癌中的临床研究进展

小细胞肺癌(small cell lung cancer,SCLC)是分化较差的高级别肺神经内分泌肿瘤,尽管仅占所有肺癌的14％左右,但生长迅速、较早出现转移,复发后缺少有效的治疗手段,改善SCLC治疗迫在眉睫.近年来,肿瘤免疫治疗展现了良好的前景,尤其程序性死亡受体1(programmed death1,PD-1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T-lymphocyte-associated antigen 4,CTLA-4)抑制剂的研究正在改变多种实体瘤的临床实践.SCLC与吸烟密切相关,具有较高的肿瘤突变负荷,是免疫治疗潜在理想的肿瘤类型.本文将总结免疫治疗在SCLC的临床研究进展,探讨SCLC免疫治疗中存在的问题、面临的挑战以及未来的应用前景.     

恶性肿瘤患者免疫治疗相关肝不良事件的影响因素

目的探讨恶性肿瘤患者免疫治疗相关肝毒性的临床特征及其影响因素。方法回顾性分析2016年1月至2019年3月就诊于中国医学科学院肿瘤医院深圳医院南山肿瘤中心和华中科技大学协和深圳医院接受免疫检查点抑制剂治疗的112例恶性肿瘤患者的临床资料,其中男64例,女48例;中位年龄60岁。结果112例患者中,肝不良事件发生率为26.8%(30/112),3~5级肝不良事件发生率为7.14%(8/112),出现肝不良事件的中位时间为接受免疫治疗后3周。单因素及多因素分析均显示,患者肝不良事件的发生与肝癌有关(P<0.05)。发生3~5级肝不良事件患者接受规范甲强龙治疗后,4~6周内肝功能恢复。结论肝癌为恶性肿瘤患者免疫治疗发生相关肝脏不良事件的危险因素。     

Immune evasion mechanisms and therapeutic strategies in gastric cancer

Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.     

放疗联合免疫检查点抑制剂在胶质母细胞瘤治疗中的研究进展

胶质瘤是颅内最常见的原发性肿瘤,大部分患者表现为胶质母细胞瘤,发病率及致死率极高。尽管胶质母细胞瘤患者经过手术切除联合放、化疗的标准化治疗,但预后仍然很差。近年来,免疫治疗在多种实体肿瘤治疗中取得了突破性进展,但现有数据显示免疫治疗对提高胶质母细胞瘤患者生存期的效果不佳。然而研究表明,免疫治疗可以与放疗产生协同效应,放疗可以增加抗原呈递,并促进促炎性肿瘤微环境的形成,为免疫治疗提供更多相关靶点。本文旨在讨论放疗对肿瘤免疫微环境的影响,以及放疗联合免疫检查点抑制剂在胶质母细胞瘤治疗中的作用。     

胰腺导管腺癌免疫治疗研究现状和展望

胰腺导管腺癌(Pancreatic ductal adenocarcinoma,PDAC)是胰腺癌最常见的类型,预后极差。手术切除是目前唯一的根治手段,但多数患者就诊时已失去手术机会。免疫治疗作为一种新兴的治疗手段,在多种实体瘤和血液系统恶性肿瘤治疗中显现出乐观前景。然而,PDAC肿瘤抗原性低以及免疫抑制微环境等特征导致其免疫治疗困难重重。本文通过综述PDAC的肿瘤微环境组成特点和目前开展的新型免疫治疗策略,为PDAC的免疫治疗研究提供新思路。     

免疫耐受与肿瘤的发生

近年来,研究表明肿瘤免疫与肿瘤的发生、诊断、治疗及预后等密切相关,肿瘤细胞逃避免疫系统的机制正在备受关注,免疫耐受是肿瘤细胞逃避免疫系统作用的重要方式,也是肿瘤发生的重要机制之一.其中p53基因、调节性T细胞、吲哚胺2,3双加氧酶在肿瘤免疫耐受中的作用逐渐成为研究的热点.     

免疫微环境与肿瘤关系的研究进展

近年研究表明,肿瘤组织中的免疫成分,如各类免疫细胞及其他间质细胞与肿瘤细胞产生的生长因子、细胞因子、促进血管生成因子等协同作用,促进了肿瘤的发生发展.文章就肿瘤免疫微环境和肿瘤发生发展的研究进展作一综述.     

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

Sarcomas are a heterogenous group of mesenchymal cancers comprising over 100 subtypes. Current chemotherapy for all but a very few subtypes has limited efficacy, resulting in 5-year relative survival rates of 16% for metastatic patients. While sarcomas have often been regarded as an “immune cold” tumor category, recent biomarker studies have confirmed a great deal of immune heterogeneity across sarcoma subtypes. Reports from the first generation of clinical trials treating sarcomas with immunotherapy demonstrate a few positive responses, supporting efforts to stratify patients to optimize response rates. This review summarizes recent advances in knowledge around immune biomarker expression in sarcomas, the potential use of new technologies to complement these study results, and clinical trials particularly of immune checkpoint inhibitor therapy in sarcomas.Each of the immune biomarkers assessed was reviewed for subtype-specific expression patterns and correlation with prognosis. Overall, there is extensive heterogeneity of immune biomarker presence across sarcoma subtypes, and no consensus on the prognostic effect of these biomarkers. New technologies such as multiplex immunohistochemistry and high plex in situ profiling may offer more insights into the sarcoma microenvironment. To date, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits. Combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma and alveolar soft-part sarcoma. Better understanding of the sarcoma immune status through biomarkers may help decipher the reasons behind differential responses to immunotherapy.     

应激对肿瘤转移的影响及其免疫机制

近交系C_(57)BL雌性小鼠,经连续7天渐增强度的电刺激以复制应激状态,观察其对B_(16)黑色素瘤转移及免疫反应的影响。结果表明:1、连续电刺激7天,静脉注射瘤细胞后追加电刺激3天,于瘤细胞注射后第18天处死小鼠。应激鼠的肺表面转移结节数明显高于对照鼠(P <0.01)。2、应激鼠体内巨噬细胞(Mφ)的吞噬功能明显低于对照鼠(P<0.005)。3、应激鼠的抗体生成能力明显低于对照鼠(P< 0.001)。4、应激鼠的迟发型变态反应明显低于对照鼠(P<0.001)。5、应激鼠T淋巴细胞对有丝分裂原ConA的反应明显低于对照鼠(P<0.002)。此外,应激鼠表现为肾上腺增大,胸腺及脾重量减轻。由此表明:应激促进肿瘤转移作用与它所引起的机体免疫抑制有关。提示在临床肿瘤治疗中不可忽视应激对肿瘤转移及预后的不良影响。     

原发性肺癌患者红细胞免疫功能检测及意义

目的　观察肺癌患者的红细胞免疫功能状态及其临床意义。方法　使用“郭峰法”检测24例肺癌患者外周血中RBCC3bRR、RBCICR、CIC的含量及其手术前、后的变化,并与对照组进行比较分析。结果　肺癌组术前RBCC3bRR明显降低,CIC明显增高,与对照组比较均有非常显著差异(P<0.01)。术后红细胞免疫功能明显改善。结论　检测肺癌患者的红细胞免疫功能可能有助于肺癌的诊断、判断疗效和监测预后。     

肿瘤患者血清细胞因子水平的变化

目的探讨肿瘤患者免疫偏斜状态及化疗对其的纠正作用.方法采用ELISA法测定了肿瘤患者血清IL-2、IL-4、TNF-α、IFN-γ的水平及一线化疗后上述细胞因子的变化.结果与正常人对照,IFN-γ及TNF-α呈显著下降,而IL-2和IL-4变化不显著.正常人IFN-γ266±193.5pg/ml,TNF-α291.2±64.8pg/ml,IL-2346.2±198.2pg/ml,IL-4148.9±47.8pg/ml.带瘤组IFN-γ45.8±31.2pg/ml,TNF-α62.5±142pg/ml,IL-2552.3±742.5pg/ml,IL-4240.1±224.3pg/ml.术后组IFN-γ36.4±18.8pg/ml,TNF-α32.7±15.1pg/ml,IL-2245.1±123pg/ml,IL-4121.6±107.5pg/ml.化疗后IFN-γ和TNF-α均有不同程度回升.带瘤组化疗前IFN-γ38.4±29pg/ml,TNF-α18.1±14pg/ml;化疗后IFN-γ62±59.4pg/ml,TNF-α35.4±25.2pg/ml.术后组化疗前IFN-γ45.8±57.2pg/ml,TNF-α26.8±12.7pg/ml;化疗后IFN-γ64.5±68.3pg/ml,TNF-α32.9±15.9pg/ml.结论肿瘤患者细胞因子网络调节失衡,化疗药物对其有一定调整作用.     

基于免疫检查点PD-1的肿瘤免疫耐药机制及耐药后再治疗的策略

免疫治疗被认为是继手术、放疗和化疗后的第四种肿瘤治疗方法。近年来随着对免疫治疗特别是免疫检查点抑制剂研究的深入,PD-1/PD-L1通路抑制剂被批准用于许多癌种的治疗,但由于肿瘤细胞通过多种耐药机制规避免疫应答,免疫检查点阻断存在整体应答率低、原发或继发性耐药等难题。本文阐述了肿瘤免疫耐药的机制,探讨了耐药后再治疗的策略,为提高免疫检查点抑制剂的应答率、降低免疫耐药发生的概率提供理论和临床依据。     

Molecular Profiling of the Metaplastic Spindle Cell Carcinoma of the Breast Reveals Potentially Targetable Biomarkers

IntroductionSpindle cell carcinoma is a rare subtype of metaplastic breast cancer, with triple-negative (TNBC: estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative) phenotype. It is associated with a marked resistance to conventional chemotherapy and has an overall poor outcome.Materials and MethodsTwenty-three pure spindle cell carcinomas of the breast (18 primary and 5 recurrent/metastatic) were comprehensively explored for biomarkers of immuno-oncology and targeted therapies using immunohistochemistry and DNA/RNA sequencing.ResultsThe majority (21/23) of spindle cell carcinomas were TNBC. Estrogen and androgen receptor expression above the therapeutic thresholds were detected in 2 cases each. Pathogenic gene mutations were identified in 21 of 23 cases, including PIK3CA, TP53, HRAS, NF1, and PTEN. One case with matched pre- and post-chemotherapy samples exhibited a consistent mutational profile (PIK3CA and HRAS mutations) in both samples. Gene amplifications were present in 5 cases, including 1 case without detectable mutations. The spindle cell carcinomas cohort had consistently low total mutational burden (all below the 80th percentile for the entire TNBC cohort). All tumors were microsatellite stable. Programmed death-ligand 1 expression was observed on both tumor cells (in 7/21 cases), and in tumor-infiltrating immune cells (2/21 cases).ConclusionsSpindle cell carcinomas are characterized by targetable molecular alterations in the majority of cases, but owing to the lack of uniform findings, individual patient profiling is necessary. Detection of individual combinations of biomarkers should improve treatment options for this rare but aggressive disease.     

溶瘤病毒诱导肿瘤凋亡及激活抗肿瘤免疫机制的研究进展

恶性肿瘤被认为是细胞不受控制的生长和增殖。肿瘤细胞为避免被清除,形成多种自我保护机制,其中包括对细胞凋亡的抵抗,以及通过影响免疫系统形成的免疫逃逸。这使得肿瘤细胞具有很强的增殖能力,并产生高度的侵袭、转移倾向。部分肿瘤患者,在接受治疗时,效果并不理想或在治疗后,仍然出现复发、转移的情况。因此,新的治疗方式的研发是当务之急。溶瘤病毒的发现为恶性肿瘤的治疗提供了新思路。随着对溶瘤病毒的深入研究,人们发现溶瘤病毒可以通过多种机制发挥抗肿瘤作用,除了在肿瘤细胞中复制、引起肿瘤细胞的裂解,还能够诱导肿瘤细胞发生凋亡。此外,溶瘤病毒通过激活免疫细胞从而,启动抗肿瘤免疫应答并改变肿瘤细胞周围的免疫微环境来发挥长效的抗肿瘤作用,并抑制未感染病毒的肿瘤细胞。溶瘤病毒能够同时针对细胞凋亡以及机体抗肿瘤免疫发挥作用使其可以有效地对抗肿瘤细胞的凋亡抵抗和免疫逃避,使得它作为潜在的抗肿瘤治疗方式受到广泛关注。本文旨在介绍溶瘤病毒通过诱导肿瘤细胞凋亡以及激活免疫系统进而发挥抗肿瘤作用的相关研究进展。