精准肿瘤医学之实践：靶向肿瘤免疫微环境

近年来,肿瘤免疫治疗技术的发展为拓宽精准肿瘤医学领域做出了巨大贡献。免疫微环境是影响免疫治疗效果的重 要因素,其在肿瘤进展和动员抗肿瘤免疫方面都有不可忽视的作用。针对肿瘤免疫微环境的免疫性放疗、免疫检查点抑制剂、肿 瘤疫苗和免疫细胞治疗等手段已在临床研究中取得了很多成果,但其临床疗效仍有待提高。本文在介绍肿瘤免疫微环境的组成 和特征的基础上,从临床应用的角度阐述针对目前靶向肿瘤免疫微环境的治疗手段可行的优化策略。     

免疫微环境促进肿瘤发生发展的机制研究进展

机体免疫有宿主保护和肿瘤促进双重作用免疫微环境对肿瘤的促进作用知之甚少。研究发现本文讨论免疫微环境可直接或间接地影响肿瘤的发生发展,其机制。其机制包括促进肿瘤血管生成、改变肿瘤的生物学特性、筛选适应微环境的肿瘤细胞存活或建立适宜的肿瘤微环境促进肿瘤进展,甚至可以调节肿瘤干细胞活性。基于免疫微环境在肿瘤发生发展中的重要作用,免疫治疗成为一种重要的抗肿瘤治疗手段,而探索免疫治疗和细胞毒药物或分子靶向药物联合的多模式治疗可能是未来肿瘤免疫治疗的方向。     

肿瘤微环境对胃癌免疫治疗的影响

胃癌是消化系统死亡率较高的恶性肿瘤,手术切除、放疗、化疗等仍是目前主要的治疗手段,但效果并不理想。随着免疫学研究的发展,免疫治疗成为肿瘤综合治疗中研究的热点,许多新兴的手段如肿瘤疫苗、免疫卡控点治疗等展现出良好的应用前景。由于胃癌发病机制复杂,肿瘤异质性明显,还有很多问题亟待解决,肿瘤微环境是影响肿瘤的发生、发展、转移的重要因素,本文就肿瘤微环境对胃癌免疫治疗的影响方面的研究成果作一综述。     

免疫微环境对髓母细胞瘤免疫治疗影响的研究进展

髓母细胞瘤（medulloblastoma,MB）是儿童最常见的恶性脑肿瘤。患者通过标准的手术切除联合放、化疗能够获得长期生存,但需要承受严重的神经、内分泌系统功能障碍,因此,毒副作用小且有效的治疗方法成为临床治疗MB的迫切要求。免疫治疗是一种新兴的肿瘤治疗方法,在部分脑外肿瘤和胶质瘤治疗领域中进展迅速,但在MB中免疫治疗往往以失败告终,这与其复杂的免疫微环境有关。深入探讨MB免疫微环境的组成与功能,有助于我们发现更有效的免疫治疗方法。该综述总结分析了目前MB免疫微环境及其对MB治疗影响的研究进展,旨在为提高MB免疫治疗的有效性提供理论依据。     

胰腺癌免疫治疗的现状及前景CSCD

胰腺癌(胰腺导管腺癌)是一种恶性程度较高,诊断和治疗都较困难的消化系统恶性肿瘤。近年来,肿瘤免疫治疗在多种肿瘤中如黑色素瘤、膀胱癌、乳腺癌、非小细胞肺癌和肾癌等均取得了令人振奋的治疗效果,但是胰腺癌的免疫治疗策略尚在不断探索中。目前针对胰腺癌独特的肿瘤微环境设计了多种免疫治疗策略,包括强化/提高自身免疫反应(免疫调节剂、单克隆抗体、肿瘤疫苗和细胞治疗)以及抑制肿瘤免疫逃逸(免疫检查点抑制剂和肿瘤微环境)等。本文就胰腺癌免疫治疗的研究进展进行综述,着重探讨PD-1/PD-L1抑制剂在胰腺癌中的应用,并分析免疫治疗联合其他方式治疗胰腺癌的前景。     

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。     

基于肿瘤免疫微环境联合免疫治疗卵巢癌的研究进展

卵巢癌在女性生殖道恶性肿瘤中致死率最高,既往的标准治疗是手术加化疗,近几年以聚腺苷二磷酸核 糖聚合酶抑制剂为主的靶向治疗延长了部分患者的生存期,但仍然会面临耐药及复发。近年免疫治疗发展迅速,然 而已有的临床研究表明单一的免疫治疗在卵巢癌中疗效有限。肿瘤免疫微环境中免疫抑制性网络,在卵巢癌的发 生发展中起着重要作用,深入探索其机制有助于制定卵巢癌免疫治疗策略。本文综述了肿瘤免疫微环境与卵巢癌 的相互作用,针对免疫微环境,免疫治疗联合化疗和靶向治疗,以及过继细胞治疗等治疗方式的研究进展,为卵巢癌 得到长期持久的个性化治疗提供理论依据。     

胃癌免疫检查点抑制剂作用机制及最新研究进展

胃癌治疗有限,预后较差。目前肿瘤免疫治疗因其显著的生存获益已成为除手术、化疗、放疗及靶向治疗之外有效的新型肿瘤治疗手段。免疫检查点抑制剂作为肿瘤免疫治疗的之一,已被批准用于多种肿瘤的治疗,提示胃癌免疫治疗时代已经到来。本文介绍了免疫治疗中免疫检查点抑制剂的作用机制及相关研究进展。     

Ⅲa（N2）期非小细胞肺癌治疗进展

Ⅲa(N2)期NSCLC患者存在明显的生存差异,治疗方式的选择存在争论,是需要多学科综合治疗的异质性群体。手术从最重要的治疗方式演变为主要治疗方式之一,未来的地位可能进一步弱化;放疗随着技术层面的进步,将扮演更加重要的角色;化疗与免疫治疗的结合应得到更多的重视,需进一步阐明机理;靶向治疗与免疫检查点抑制剂在该类型患者中的应用值得进一步的研究。肿瘤细胞和宿主免疫系统在免疫微环境中通过相互作用促进免疫逃避并导致肿瘤的复发及转移,目前通过PD途径抗肿瘤等免疫治疗产品已经应用于临床并取得一定成效,该治疗原理主要依赖于浸润到肿瘤和肿瘤微环境中的效应T细胞的功能。根据肿瘤细胞周围免疫细胞（主要为T细胞等）浸润情况,相关研究确立了新型免疫表型分类,为患者治疗和预后提供思路及方向,免疫微环境值得进一步探讨。免疫治疗成为继手术、放化疗等传统治疗方法后一种新的重要治疗手段,为抗肿瘤治疗带来了巨大希望。     

免疫微环境介导的肿瘤耐受机制及其靶向治疗

免疫细胞与其分泌的细胞因子相互作用共同构成免疫微环境,在肿瘤治疗耐受过程中扮演着重要角色.免疫微环境能够通过启动抗凋亡通路、介导免疫耐受、诱导上皮间质转化及形成肿瘤干细胞等途径促进肿瘤产生治疗耐受,降低肿瘤治疗疗效.肿瘤免疫治疗已成为目前肿瘤治疗研究领域的热点.     

Inflammatory cytokines in human pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with poor prognosis. Despite extensive efforts, the current treatment methods have limited success. Therefore, novel therapeutic approaches are required. The pancreatic tumor microenvironment is rich in growth factors and inflammatory cytokines that support tumor growth, and it is highly immunosuppressive. Up-regulation of cytokine pathways has been shown to modulate PDAC progression and immune evasion; therefore targeting cytokines may have therapeutic benefits. In this review we provide an overview of current understanding of pro- and anti-inflammatory cytokines in pancreatic cancer and their potential as therapeutic targets.     

Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity?

The genomic-plasticity of the immune system creates a broad immune repertoire engaged to tackle cancer cells. Promising clinical activity has been observed with several immune therapy strategies in solid tumors including melanoma, lung, kidney, and bladder cancers, albeit as yet immunotherapy-based treatment approaches in pancreatic ductal adenocarcinoma (PDAC) remain to have proven value. While translational and early clinical studies have demonstrated activation of antitumor immunity, most recent late-phase clinical trials have not confirmed the early promise in PDAC except in MSI-High PDAC patients. These results may in part be explained by multiple factors, including the poorly immunogenic nature of PDAC along with immune privilege, the complex tumor microenvironment, and the genetic plasticity of PDAC cells. These challenges have led to disappointments in the field, nonetheless they have also advanced our understanding that may tailor the future steps for immunotherapy for PDAC. Therefore, there is significant hope that progress is on the horizon.     

Future of immunotherapy in pancreas cancer and the trials,tribulations and successes thus far

Pancreas ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of 10%. Currently, chemotherapy remains the standard of care for systemic treatment. Immunotherapy with checkpoint inhibitors unfortunately has not been found to be effective in the treatment of PDAC to date, likely due to the highly desmoplastic and immunosuppressive tumor microenvironment (TME). Treatment targeting pathways against the immunosuppressive mechanisms of PDAC are of mounting interest to improve outcomes in PDAC. In this review, we discuss prior efforts and the current state of immunotherapy in PDAC. We will also review the emerging targets and treatments with significant clinical potential for the treatment of PDAC such as: CD40 pathway, the adenosine pathway, the CXCR4/CXCL12 axis, the CCR2/CCL2 axis, IDO pathway, and others.     

Pancreatic ductal adenocarcinoma: Treatment hurdles,tumor microenvironment and immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with an average 5-year survival rate of less than 10%. Unfortunately, the majority of patients have unresectable, locally advanced, or metastatic disease at the time of diagnosis. Moreover, traditional treatments such as chemotherapy, surgery, and radiation have not been shown to significantly improve survival. Recently, there has been a swift increase in cancer treatments that incorporate immunotherapy-based strategies to target all the stepwise events required for tumor initiation and progression. The results in melanoma, non-small-cell lung cancer and renal cell carcinoma are very encouraging. Unfortunately, the application of checkpoint inhibitors, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies, in pancreatic cancer has been disappointing. Many studies have revealed that the PDAC microenvironment supports tumor growth, promotes metastasis and consists of a physical barrier to drug delivery. Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect. In this review, we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist. Particular emphasis is given to the role of the tumor microenvironment, and some of the latest and most promising studies on immunotherapy in PDAC are also presented.     

淋巴瘤微环境与免疫逃逸关系的研究进展

淋巴瘤微环境是影响淋巴瘤发生、发展的重要因素,参与调控机体免疫系统对淋巴瘤细胞的识别和免疫应答。在淋巴瘤的免疫治疗时代,微环境的状态也影响了基于单克隆抗体、小分子化合物等免疫靶向药物对淋巴瘤细胞的作用。其中,微环境相关的免疫逃逸是导致淋巴瘤治疗失败的重要因素之一。文章就基质细胞免疫细胞亚群、血管增生、缺氧状态、免疫检查点等微环境因素和免疫逃逸的相关研究最新进展进行综述。     

Targeting cancer cell metabolism in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer death by 2030. Current therapeutic options are limited, warranting an urgent need to explore innovative treatment strategies. Due to specific microenvironment constraints including an extensive desmoplastic stroma reaction, PDAC faces major metabolic challenges, principally hypoxia and nutrient deprivation. Their connection with oncogenic alterations such as KRAS mutations has brought metabolic reprogramming to the forefront of PDAC therapeutic research. The Warburg effect, glutamine addiction, and autophagy stand as the most important adaptive metabolic mechanisms of cancer cells themselves, however metabolic reprogramming is also an important feature of the tumor microenvironment, having a major impact on epigenetic reprogramming and tumor cell interactions with its complex stroma. We present a comprehensive overview of the main metabolic adaptations contributing to PDAC development and progression. A review of current and future therapies targeting this range of metabolic pathways is provided.     

基于肿瘤免疫微环境的肝癌分子分型研究进展

免疫治疗改善了肝癌整体治疗策略,其特有的免疫异质特征和对免疫微环境的高度耐受使免疫治疗进入瓶颈阶段,因此对于可能受益于免疫检查点治疗的患者来说,划分肝癌分子分型是必要的。随着二代测序技术的进步,科学家根据浸润性免疫细胞丰度、免疫检查点表达水平、多组学数据、免疫抑制互斥机制及肿瘤微环境异质性等各个层面进行分子分型探索,不仅将肝癌特定生物学、分子和临床病理特征与肿瘤微环境关联,而且显示出与转录组分子分型的重叠之处,有利于未来肝癌的诊断、治疗方式选择和预测临床结局,推动精确的肝癌个体化免疫治疗。     

Systemic Therapy for Patients With Pancreatic Cancer: Current Approaches and Opportunities for Novel Avenues Toward Precision Medicine

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year overall survival of 11%. The disease is usually diagnosed at advanced stages, and systemic chemotherapy is the standard-of-care treatment for the majority of patients with PDAC. Although novel treatment options, such as targeted therapy and immunotherapy, have achieved substantial progress leading to practice-changing results, with FDA approvals for several solid tumors so far, the progress achieved for PDAC is relatively limited. Recent studies uncovered potential therapeutic targets for patients with PDAC, and potential therapeutic opportunities are currently being further examined. Herein, we review recent advances in systemic therapy regimens, including cytotoxic agents, targeted therapies, immunotherapy, and novel therapeutic options for managing patients with PDAC. We also elaborate on molecular profiling to guide treatment and existing therapeutic opportunities that may further advance the clinical care of patients with this devastating disease.