结直肠癌患者抗程序性死亡受体1/程序性死亡受体-配体1治疗相关生物标志物的研究进展

近年来, 抗程序性死亡受体1(PD-1)/程序性死亡受体-配体1(PD-L1)的免疫治疗给中晚期结直肠癌患者带来了新的曙光, 但研究者却发现并非所有的结直肠癌患者都能从抗PD-1/PD-L1的免疫治疗中获益。因此, 精准筛选出结直肠癌患者抗PD-1/PD-L1治疗的获益人群成为当前重大难题。随着精准诊疗理念的迅速发展以及循证医学证据的不断积累, 为筛选结直肠癌免疫治疗的获益人群提供了有力帮助。通过人体生物标志物的差异来预测结直肠癌患者免疫治疗的疗效成为当下热点。生物标志物是免疫治疗的重大突破, 不仅可以筛选出结直肠癌免疫治疗的获益人群, 还能够避免无效治疗以及不良反应。本文通过回顾近期文献, 阐述结直肠癌患者抗PD-1/PD-L1治疗下生物标志物的研究现状及未来发展。     

胰腺导管腺癌的免疫治疗研究进展

胰腺导管腺癌（PDAC）是常见的消化系统恶性肿瘤,恶性程度高,容易发生转移,手术切除率低。近年来,以程序性细胞死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）抗体为代表的免疫检查点抑制剂在肿瘤的免疫治疗中取得了重大进展。然而,由于PDAC独特的肿瘤微环境及低免疫原性,PDAC的免疫治疗并不尽如人意。结合PDAC的微环境特点,笔者介绍免疫检查点抑制剂、过继细胞免疫以及肿瘤疫苗等在PDAC治疗中的进展和潜在的应用前景。     

结直肠癌微卫星稳定状态和程序性死亡、吲哚胺2,3-双加氧酶关系的研究进展

除了根治性手术、放化疗外,免疫治疗成为近年来结直肠癌（CRC）治疗的热门研究领域。随着对免疫微环境的深入研究和分子生物学技术的发展,程序性死亡受体1(PD-1)抑制剂nivolumab和pembrolizumab已被批准用于微卫星不稳定（MSI）的CRC患者。PD-1抑制剂通过阻断PD-1/程序性死亡配体1(PD-L1)通路来阻断肿瘤细胞的免疫逃逸,最终杀灭肿瘤细胞。吲哚胺2,3-双加氧酶（IDO）作为一种将色氨酸分解为犬尿氨酸的酶,其本身以及下游代谢产物都在免疫微环境中起着重要作用。IDO和PD-1/PD-L1在肿瘤免疫逃逸中发挥关键作用。本文探讨了肿瘤免疫逃逸中IDO与PD-1/PD-L1的联系以及免疫检查点和错配修复基因的相互关系。同时,微卫星状态与PD-1/PD-L1和IDO表达之间的关系仍需进一步研究和验证,从而有助于指导肿瘤免疫治疗,提高患者生存质量,延长预期寿命。     

纳米刀消融联合程序性死亡蛋白-1/程序性死亡蛋白配体-1治疗胰腺癌及其免疫学机制研究进展

胰腺癌特殊的肿瘤微环境不利于免疫治疗,而纳米刀消融可在一定程度上逆转免疫抑制,使其成为目前唯一适用于胰腺癌的消融治疗方法。动物研究结果证实,纳米刀消融联合程序性死亡蛋白-1（PD-1）/程序性死亡蛋白配体-1（PD-L1）治疗胰腺癌可延长患者生存时间。本文对纳米刀消融联合PD-1/PD-L1治疗胰腺癌及其免疫学机制研究进展进行综述。     

程序性死亡受体-1及其配体抑制剂在结直肠癌中的研究进展

目的总结程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)抑制剂及其联合治疗在结直肠癌中的研究进展并为结直肠癌提供新的治疗方向。方法收集近年来PD-1/PD-L1抑制剂在结直肠癌中应用的研究进展的相关文献并进行综述。结果针对PD-1/PD-L1通路的抗体在结直肠癌患者的临床试验中取得了一定的研究成果,尤其是在高频微卫星不稳定患者中效果更佳,多种抗体联合治疗以及其与化疗、靶向治疗联合应用方案具有更好的生存获益。结论 PD-1/PD-L1抑制剂在高频微卫星不稳定结直肠癌生存获益方面具有一定疗效,尤其是联合方案显示出更好的效果。     

程序性死亡受体1及其配体抑制剂治疗骨肉瘤的研究进展

新辅助化疗结合手术治疗使骨肉瘤患者的5年生存率超过50%,但是,合并复发或转移的骨肉瘤患者其预后仍较差。免疫检查点抑制剂是近年肿瘤领域的研究热点,其中针对程序性死亡受体1及其配体(PD-1/PD-L1)的免疫治疗已在多种人类肿瘤治疗中取得较好疗效。随着肿瘤免疫研究的不断深入,包括PD-1/PD-L1抑制剂在内的免疫治疗在骨肉瘤综合治疗中已发挥越来越重要的作用。该文对PD-1/PD-L1抑制剂治疗骨肉瘤的研究现状进行综述,希望为骨肉瘤的免疫治疗研究提供参考。     

PD-1/PD-L1与肿瘤相关巨噬细胞在肿瘤发生中的相互作用研究进展

程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）和肿瘤微环境中的肿瘤相关巨噬细胞（TAMs）与肿瘤的发生密切相关。TAMs又主要分为抗肿瘤作用的M1型和促肿瘤作用的M2型,而肿瘤组织中浸润的巨噬细胞主要以M2-TAMs为主。近年的研究进展主要为PD-1/PD-L1轴抑制TAMs的抗肿瘤作用,TAMs分泌的细胞因子、趋化因子、外泌体等参与调节PD-1/PD-L1的表达等方面。笔者就PD-1/PD-L1与TAMs在肿瘤发生中的作用进行综述,同时也对两者之间可能存在的相互作用进行了归纳,探讨靶向调控TAMs的功能对PD-1/PD-L1单抗治疗肿瘤效果的影响。     

PD-1/PD-L1抑制剂在胃癌中的研究现状

目的阐述程序性死亡受体蛋白-1(PD-1)及其配体-1(PD-L1)抑制剂在胃癌中的研究现状,了解PD-1/PD-L1抑制剂存在的关键问题,为以后的研究提供理论基础。方法复习经典及最新有关免疫治疗,尤其是PD-1/PD-L1抑制剂的文献并综述之。结果PD-1/PD-L1抑制剂是目前肿瘤免疫治疗研究中的热点,派姆单抗及纳武单抗在临床免疫抑制剂治疗研究中较常用,继在血液系统恶性肿瘤和恶性黑色素瘤中展示出良好疗效后,二者在胃癌临床研究中也取得了较大成功。在一些临床研究中,PD-1/PD-L1抑制剂治疗患者相较常规化疗患者总生存期延长,尤其是在PD-1阳性患者中的疗效更为显著,但是其研究仍存在无法精确预测受益人群、肿瘤免疫超进展等亟待解决的问题,可喜的是,目前肿瘤免疫基础研究成果日益增多,为解决这些问题在理论方面提供了有力支撑。结论PD-1/PD-L1抑制剂等肿瘤免疫抑制剂疗法为胃癌患者的治疗提供了新思路,尽管其在临床研究中仍存在较多问题,但随着研究的进一步深入,PD-1/PD-L1抑制剂必将成为晚期胃癌患者治疗的利器之一。     

肝癌肝移植术后复发转移的免疫治疗

原发性肝癌(肝癌)是我国肝移植的主要适应证之一,但肝癌肝移植受者术后5年生存率不足50%,术后复发转移是影响受者长期生存的主要原因。目前,以程序性细胞死亡蛋白1(PD-1)/程序性细胞死亡蛋白配体1(PD-L1)免疫检查点抑制剂为代表的免疫治疗在中晚期肝癌治疗中取得显著疗效,但其在肝癌肝移植术后肿瘤复发转移受者中能否应用尚有较多争议,主要原因在于其在发挥作用的同时可能会引起急性排斥反应。本文总结了免疫治疗在肝癌肝移植术后复发转移受者中的应用进展,以期通过免疫治疗改善肝癌肝移植受者的生存率。     

PD-1/PD-L1抑制剂在尿路上皮癌免疫治疗中的研究进展

局部进展或转移性尿路上皮癌的患者在铂类化疗失败后的治疗手段十分有限。发展新的治疗方法,尤其是针对一线化疗失败后的病例显得尤为重要。程序性死亡分子1(PD-1)/程序性死亡受体配体1(PDL1)、细胞毒性T淋巴细胞相关蛋白4(CTLA-4)免疫抑制剂在包括尿路上皮癌在内的多种肿瘤治疗中取得了较为满意的疗效,与常规化疗相比,安全性和耐受性较好,患者总生存获益明显。Atezolizumab、Avelumab、Durvalumab、Nivolumab和Pembrolizumab为5个获批用于治疗尿路上皮癌的免疫检查点抑制剂,可能将重新定义尿路上皮癌的治疗标准,然而相当比例的尿路上皮癌患者对PD-1/PD-L1通路抑制剂无应答,蛋白水平表达的PD-L1在预测免疫检查点抑制剂的临床疗效存在一定的局限性。本文将对抗PD-1/PD-L1免疫治疗在尿路上皮癌中的研究进展作一综述。     

Advances in systemic chemotherapy and immunotherapy for metastatic colorectal cancer

Colorectal cancer is the second leading cause of cancer related death in the United States. Approximately 25% of patients are diagnosed with metastatic colorectal cancer (mCRC) and the 5-year survival rate in mCRC is low at 14%. Primary treatment for mCRC is systemic therapy, which includes chemotherapy, immunotherapy, and targeted agents. With advances in genomic profiling, we can now tailor treatment to unique patient populations and improve overall survival. In this review, we discuss treatment strategies for mCRC patients based on tumor sidedness, KRAS/BRAF wild-type versus mutant tumors, and review the benefit of immunotherapy in microsatellite unstable and mismatch repair deficient tumors.     

循环肿瘤细胞PD-L1表达在非小细胞肺癌免疫治疗中的应用

肺癌是全世界发病率及病死率最高的恶性肿瘤。近年来,针对程序性死亡受体1(programmed cell death 1,PD-1)及其配体(programmed cell death-ligand 1,PD-L1)的免疫检查点抑制剂治疗显著改善了非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的预后。然而在非选择人群中免疫治疗的客观应答率仅约20%,因此选择出免疫治疗潜在的获益人群非常重要。通过免疫组织化学检测肿瘤组织中PD-L1的表达可以在一定程度上预测免疫治疗的疗效,但是其仍有一定的局限性。最新临床研究表明循环肿瘤细胞(circulating tumor cell,CTC)上PD-L1的表达(PD-L1 expression in circulating tumor cells,CTC-PD-L1)是一种潜在的独立生物标志物,其可为NSCLC的免疫治疗提供重要信息。本文将对CTC-PD-L1检测技术及其在NSCLC患者免疫治疗效果中的预测价值及最新临床研究进展进行综述。     

Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors.

Inactivation of deoxyribonucleic acid (DNA) mismatch repair genes, most commonly human mutL homologue 1 (hMLH1) or human mutS homologue 2 (hMSH2), is a recently described alternate pathway in cancer development and progression. The resulting genetic instability is characterized by widespread somatic mutations in tumor DNA, and is termed high-frequency microsatellite instability (MSI-H). Although described in a variety of tumors, mismatch repair deficiency has been studied predominantly in colorectal carcinoma. Most MSI-H colorectal carcinomas are sporadic, but some occur in patients with hereditary nonpolyposis colorectal cancer (HNPCC), and are associated with germline mutations in mismatch repair genes. Until now, the identification of MSI-H cancers has required molecular testing. To evaluate the role of immunohistochemistry as a new screening tool for mismatch repair-deficient neoplasms, the authors studied the expression of hMLH1 and hMSH2, using commercially available monoclonal antibodies, in 72 formalin-fixed, paraffin-embedded tumors that had been tested previously for microsatellite instability. They compared immunohistochemical patterns of 38 MSI-H neoplasms, including 16 cases from HNPCC patients with known germline mutations in hMLH1 or hMSH2, with 34 neoplasms that did not show microsatellite instability. Thirty-seven of 38 MSI-H neoplasms were predicted to have a mismatch repair gene defect, as demonstrated by the absence of hMLH1 and/or hMSH2 expression. This included correspondence with all 16 cases with germline mutations. All 34 microsatellite-stable cancers had intact staining with both antibodies. These findings clearly demonstrate that immunohistochemistry can discriminate accurately between MSI-H and microsatellite-stable tumors, providing a practical new technique with important clinical and research applications.     

A review of the PD-1/PD-L1 checkpoint in bladder cancer: From mediator of immune escape to target for treatment

Purpose

Recent observations have focused attention on the means that human tumors employ to evade host defense systems critical to immune surveillance. The concepts of immunotherapy are familiar to urologists because of the use of bacillus Calmette-Guérin in bladder cancer. Research demonstrating the importance of checkpoint inhibitors in suppressing immune responses against tumors has heightened interest in immunotherapy at a time when there is a need for alternatives to bacillus Calmette-Guérin. We review the literature on the application of immunotherapeutic agents targeting a key checkpoint pathway, programmed death 1 (PD-1) and its ligand (PD-L1), in the field of bladder cancer.

胆管癌药物治疗的研究进展

胆管癌（CCA）是起源于胆道系统的恶性肿瘤,虽然手术治疗是CCA公认的根治手段,但由于胆道系统的特殊解剖特点及CCA的高侵袭性使得治疗效果并不理想。药物治疗成为晚期CCA患者获得较好预后的选择,主要分为化学治疗、靶向治疗及免疫治疗。目前研究发现了成纤维细胞生长因子受体（FGFR）及异柠檬酸脱氢酶1 (IDH-1)两个重要的治疗靶点,由此衍生出的靶向治疗药物在临床试验中普遍展现了良好的效果。虽然CCA普遍表达PD-1/PD-L1,但对于免疫检查点抑制剂不敏感,通过联合使用其他免疫治疗药物可以提高治疗效果。与新兴的靶向治疗和免疫治疗相比,传统化学治疗在CCA治疗效果最为稳定,美国国立综合癌症网络指南建议顺铂+吉西他滨为晚期不可切除或有转移症状的CCA患者的一线化疗方案。这些药物的最新进展将会显著改善CCA患者的生存获益。     

肝癌免疫治疗策略的进展与思考

中国是肝癌大国,全世界每年>50%的新发和死亡病例发生在中国。肝癌的化疗敏感性较低,以抗血管生成为主的靶向治疗是进展期肝癌的主要系统治疗手段,但能达到的有效率和生存延长作用十分有限。近年来,免疫检查点抑制剂在肝癌临床治疗中展现出较好疗效,正在改变肝癌治疗格局,但也面临诸多问题。如程序性死亡配体-1、肿瘤突变负荷、错配修复蛋白等临床常用生物标志物在肝癌的临床应用价值十分有限。与其他病因相关肝癌比较,中国乙型病毒性肝炎相关肝癌具有其独特的基因变异图谱,但基于分子分型的个体化治疗策略尚未建立。更加有效且多样化的系统治疗手段,可推动肝癌进入综合治疗新时代,相关诊断与治疗规范有待进一步探索和确立。笔者查阅相关文献,结合临床实践,探讨肝癌免疫治疗策略的进展与思考。     

Clinical development of immunotherapy for prostate cancer

Prostate cancer is the most common cancer in men, and the second leading cause of cancer‐related death in Western countries. Prostate cancer‐related death occurs in patients with metastatic castration‐resistant prostate cancer. Although several new drugs for castration‐resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.     

Interpretation of immunohistochemistry for mismatch repair proteins is only reliable in a specialized setting

We examined the validity of immunohistochemistry for mismatch repair (MMR) proteins in colorectal cancer specimens to identify patients at risk for Lynch syndrome (hereditary nonpolyposis colorectal cancer) and patients with sporadic microsatellite instable colorectal cancer. This was assessed by observer agreement for and accuracy of interpretation of immunohistochemistry. Seven pathologists from 5 different pathology laboratories evaluated 100 molecularly defined colorectal cancers stained for MLH1, PMS2, MSH2, and MSH6. Two of the pathologists were experienced in interpretation of immunohistochemistry for MMR proteins. After evaluation of a subset of 20 cases, a discussion meeting was organized, after which pathologists evaluated all 100 cases. Staining patterns were interpreted as aberrant, normal, or indefinite. In 82% of tumors, 5 or more pathologists reached the same interpretation, which was considered the consensus diagnosis. Consensus was reached slightly less frequently in microsatellite instable than in stable tumors, and interobserver variation was moderate to substantial (kappa: 0.49-0.79). More microsatellite instable tumors showed an indefinite staining pattern compared with microsatellite stable tumors. Three out of 7 pathologists, including the 2 experienced pathologists, did not miss a microsatellite instable tumor. Each pathologist found at least 1 tumor with an aberrant staining pattern, whereas consensus was a normal staining pattern and the tumor was microsatellite stable. We conclude that, if restricted to experienced pathologists, immunohistochemistry is a valid tool to identify patients at risk for Lynch syndrome and patients with sporadic microsatellite instable colorectal cancer. An indefinite or aberrant staining result has to be followed by molecular microsatellite instability analysis to confirm the presence of a defective DNA MMR system.