前列腺癌免疫治疗的热点问题：新策略和新思路

前列腺癌是一个免疫“冷肿瘤”，研究已证实单一的免疫治疗对其疗效不佳。目前正在开发基于免疫治疗的联合治疗，主要机制包括增加肿瘤抗原提呈能力、激活先天免疫通路、调节肿瘤微环境、上调程序性死亡配体1的表达以及免疫治疗的反馈增益作用。通过将一线治疗如新型内分泌治疗、放疗、化疗、多腺苷二磷酸核糖聚合酶抑制剂与免疫治疗相结合，以及免疫检查点抑制剂（ICI）与ICI或肿瘤疫苗的联合治疗，能够增加治疗潜力，为前列腺癌患者提供更多的治疗方案。     

前列腺癌的药物治疗

前列腺癌分为激素依赖型和激素非依赖型,前者对雄激素敏感,去除雄激素后细胞发生凋亡;而后者对去除雄激素无反应,发生转移后对常规肿瘤化疗药物治疗不敏感,死亡率高。对于不同类型的前列腺癌,常采用不同的药物进行治疗。     

前列腺癌治疗新靶点——脂氧合酶

前列腺癌是老年男性中较常见的疾病,分为雄激素依赖型和非雄激素依赖型两大类,后者分化度低、恶性度高,对雄激素去势治疗无应答,对常规肿瘤化疗药物治疗也不敏感,死亡率高。近年研究表明,脂氧合酶通过多种途径参与肿瘤的发生、发展和转移,同时也证实人前列腺癌组织和前列腺癌细胞株存在脂氧合酶高表达,因此,抑制脂氧合酶有可能为前列腺癌的治疗提供新的选择。     

肿瘤微环境对肿瘤免疫的影响

恶性实体肿瘤组织内微环境不同程度的存在着低pH﹑低O2、营养贫乏状态,这种状态影响了恶性肿瘤细胞对化疗药物的敏感性,不利于细胞因子﹑免疫细胞抑制杀伤恶性肿瘤细胞.该文简要叙述恶性肿瘤组织的微环境形成﹑细胞内外液特点、肿瘤免疫以及肿瘤微环境对细胞因子﹑免疫细胞和单克隆抗体抗恶性肿瘤作用影响,探讨如何改善这种微环境状态以提高恶性肿瘤的治疗效果.     

低氧激活型DNA烷化剂类抗肿瘤药TH-302

肿瘤组织中血管分布不同于正常组织,杂乱无序,导致其微环境散布着低氧区和常氧区。在血管相对丰富的常氧区,肿瘤细胞生成迅速,且对传统化疗极为敏感,而低氧区肿瘤细胞则处于休眠状态,对标准化疗和放疗具有抵抗性,成为肿瘤治疗的主要障碍。因此,有人提出,开发能杀灭低氧微环境肿瘤     

血管内皮生长因子反义核酸提高前列腺癌PC3细胞对化疗药物敏感性的研究

目的探讨血管内皮生长因子(VEGF)反义核酸对前列腺癌细胞PC3对常用化疗药物作用的影响,联合反义核酸和紫杉醇治疗裸鼠移植肿瘤。方法采用新型脂质体Oligofectamine携带VEGF反义核酸转染前列腺癌细胞PC3。定量反转录-聚合酶链反应(RT-PCR)和Western杂交的方法检测细胞VEGFmRNA和蛋白的表达,四甲基偶氮唑蓝法(MTT)检测转染反义核酸的细胞对化疗药物的敏感性,联合反义核酸和紫杉醇对裸鼠移植肿瘤进行治疗,观察肿瘤抑制率,计算药物相互作用指数(CDI)。结果新型脂质体携带VEGF反义核酸转染前列腺癌细胞PC3,与对照组和正义组比较,反义组细胞VEGFmRNA和蛋白的表达明显下降,对2种前列腺癌常用化疗药物紫杉醇和米托蒽醌的敏感性明显增强(P<0.05)。治疗裸鼠移植肿瘤28d后肿瘤生长抑制率分别为反义组58.5%,紫杉醇组60.2%,联合组84.1%,CDI=0.97。结论 VEGF反义寡核苷酸抑制VEGF的表达,提高细胞对化疗药物的敏感性,联合反义核酸和紫杉醇可以更有效地抑制肿瘤生长,并且2种药物具有协同作用。     

肿瘤疫苗在前列腺癌治疗中的研究进展

免疫治疗在过去十年中飞速发展,彻底改变了几种血液系统和实体恶性肿瘤的治疗格局,在前列腺癌(PCa)治疗中也被广泛探索,其中肿瘤疫苗更是免疫治疗中的研究热点。不过由于免疫微环境的复杂性及患者免疫系统的个体化差异,近年来PCa肿瘤疫苗的研究未能取得突破性进展。本研究旨在讨论PCa肿瘤微环境与免疫治疗发展的关系,总结了目前PCa肿瘤疫苗的相关研究进展,以及与其他疗法的联合应用的探讨,并对这种免疫学“冷”恶性肿瘤的疫苗未来研究方向进行了展望。     

增强多西他赛对前列腺癌细胞作用的靶点研究进展

靶向治疗是近年来前列腺癌治疗研究的热点.对分子和基因水平上发现的靶点进行治疗有望解决耐药性问题.目前,以多西他赛为基础的化疗在前列腺癌治疗中仍然占有重要地位,本文叙述了可用于增强多西他赛对前列腺癌细胞作用的靶点研究进展,包括(1)亮氨酸拉链肿瘤抑制因子1相关的靶点;(2)与NF-κB/IL-6相关的靶点;(3)与微RNA相关的靶点.     

MDSCs参与肿瘤微环境免疫抑制的研究进展

肿瘤的发生、发展以及转移与其所处的肿瘤微环境密切相关,肿瘤细胞可以通过自分泌和旁分泌等方式对所处环境进行改造以维持自身的生存和发展。肿瘤免疫抑制是肿瘤微环境的重要特征,越来越多的研究表明骨髓来源的抑制性细胞（myeloid-derived suppressor cells,MDSCs）在肿瘤微环境免疫抑制中扮演了重要的角色,本文就MDSCs参与肿瘤微环境免疫抑制的研究进展进行综述,以期为进一步理解与干预肿瘤免疫抑制奠定基础。     

刺激响应型聚合物在肿瘤免疫治疗方面的研究进展

肿瘤微环境刺激响应型聚合物是将肿瘤微环境独特的生理条件作为刺激因子,响应性发生结构或理化性质改变的一系列新型聚合物,具有生物相容性高、稳定性好、机体内可降解代谢、易于修饰等优点.在肿瘤治疗中,免疫治疗法以其突出的治疗效果和长效的免疫记忆而备受关注,将刺激响应型聚合物与肿瘤免疫治疗相结合有望成为肿瘤治疗的新策略.通过对肿...     

Drug resistance: challenges to effective therapy

The success of current treatment strategies is limited by the development of therapy resistance as evidenced by recurrence of the primary tumor or distant metastasis. Eradication of primary and metastatic disease requires interventions at both the cancer cell and tumor microenvironment levels. In this review, we will discuss mechanisms that are intrinsic to cancer cells, and those that are mediated by the tumor microenvironment as contributors to drug resistance. Mechanisms contributing to multidrug resistance phenotype and the challenges facing molecular targeted therapy are discussed. The DNA damage tolerance pathway confers tolerance to a variety of structurally and functionally unrelated drugs. A rationale for targeting the DNA damage tolerance pathway as a novel tool for overcoming drug resistance is discussed. We have also addressed the need for employing clinically relevant model systems for performing drug sensitivity evaluations. These model systems must take into account the three-dimensional organization and in vivo relationship of tumor with its microenvironment. Such integrative efforts would not only yield a more global understanding of the tumor- and microenvironment-derived mechanisms involved in emergence of drug resistance but would also provide novel therapeutic targets that will disrupt the interactions between the tumor cells and its microenvironment.     

Impact of immune infiltration on tumor development and progression

Recently, immune infiltration has a crucial role in modulating tumor progression and response to therapy which comprised cells from the innate and adaptive immune response. Infiltrating immune cells can be detected in biopsy specimens and exploited to promote cancer metastasis, angiogenesis and growth. Mounting evidence demonstrates that many cancer-associated cell types within the tumor stromal support tumor growth and development, greatly modifying cancer cell behavior,facilitating invasion and metastasis and controlling sensitivity to drug therapy. Furthermore,immune infiltration of the tumor microenvironment has been associated with improved survival for some patients with solid tumors which have prognostic value. Infiltrating immune cells are both prognostic and predictive of response to cancer therapies. Understanding the interactions between tumor and immune infiltration is critical to find prognostic biomarkers,reduce drug resistance, and developnew therapies.Therefore, cancer immunotherapy based on tumor-infiltrating cell populations has become arguably the most promising advancement in cancer research and therapy in recent years. In this review, we provide an updated overview of key components of the immune infiltrating cells in the tumor microenvironment and the impact of immune infiltration on tumor development and progression. Moreover, we discuss the intricacy of the reciprocal interactions between cancer-associated immune cell types and signal transduction pathways, which appear to be crucially linked to cancer progression in response to the tumor microenvironment. Finally, we focus on the current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented.     

Drug resistance and the microenvironment: nature and nurture.

Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for cancer therapy. It is well documented that cancer cells can adapt to the presence of chemotherapeutic agents through mutations or expression changes of key genes that control drug metabolism or response to damage. In addition, it is becoming increasingly apparent that the tumor microenvironment can have an important impact on the success of chemotherapy. Indeed, cell-cell and cell-matrix interactions can influence the cancer cells sensitivity to apoptosis and affect drug resistance. A model is proposed in which the tumor cells may actively reorganize their environment to maximize their survival in the presence of anticancer agents.     

Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.     

Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.     

免疫检查点抑制剂与抗血管生成药物合用治疗肿瘤的研究进展

免疫检查点抑制剂(immune checkpoint inhibitor,ICI)通过阻断免疫负调节信号激活机体的抗肿瘤免疫应答,临床试验表明,ICI仅对部分晚期癌症患者有效。而通过阻断肿瘤血管生成常用的抗血管生成药物尽管可以抑制肿瘤的生长,对患者的生存期却未体现出改善,且存在耐药等应用局限。肿瘤免疫反应与血管生成密切相关,同时,肿瘤血管生成高度依赖于免疫抑制微环境。近来一些研究表明,ICI联合血管生成抑制剂不但可以减轻其治疗耐药性,且疗效优于任何单一疗法。联合疗法加强血管正常化和免疫重编程之间的正反馈循环,调节肿瘤免疫微环境以诱导机体持久的抗肿瘤免疫反应。该文对ICI联合抗血管生成疗法的最新进展展开论述,以期为后续研究提供新的思路与借鉴。     

克服肿瘤多药耐药的药物共递送纳米载体的设计及研究新方向

多药耐药（multidrug resistance，MDR）是肿瘤治疗成功的主要障碍，药物共递送纳米载体因其肿瘤靶向、控制释放、一致的药动学曲线而被认为是克服MDR的有效策略。本综述总结了当前克服MDR的药物共递送纳米载体的设计思路，并分析了具有前景的研究方向，包括精确药物负载纳米载体、呈时序释放的纳米载体和对肿瘤微环境设计纳米载体，这些新兴策略为临床肿瘤治疗提供了新颖且更好的定制组合方案。     

Membrane-camouflaged supramolecular nanoparticles for co-delivery of chemotherapeutic and molecular-targeted drugs with siRNA against patient-derived pancreatic carcinoma

Pancreatic cancer remains one of the most lethal malignancies worldwide. The combination of the first-line standard agent gemcitabine (GEM) with the molecular-targeted drug erlotinib (Er) has emerged as a promising strategy for pancreatic cancer treatment. However, the clinical benefit from this combination is still far from satisfactory due to the unfavorable drug antagonism and the fibrotic tumor microenvironment. Herein, we propose a membrane-camouflaged dual stimuli-responsive delivery system for the co-delivery of GEM and Er into pancreatic cancer cells and tissues to block the antagonism, as well as reshapes profibrotic tumor microenvironment via simultaneous delivery of small interference RNA (siRNA) for synergistic pancreatic cancer treatment. This “all-in-one” delivery system exhibits sensitive GSH and pH-dependent drug release profiles and enhances the inhibitory effects on the proliferation and migration of tumor cells in vitro. Excitingly, the systemic injection of such a biomimetic drug co-delivery system not only resulted in superior inhibitory effects against orthotopic pancreatic tumor and patient-derived tumor (PDX), but also greatly extended the survival rate of tumor-bearing mice. Our findings provide a promising therapeutic strategy against pancreatic cancer through the enhanced synergistic effect of target therapy, chemotherapy and anti-fibrotic therapy, which represents an appealing way for pancreatic cancer treatment.     

肿瘤微环境对乳腺癌发生发展的影响

摘要： 肿瘤微环境 （TME） 在局部耐药性、 免疫逃脱和远端转移等多个肿瘤发生、 发展的步骤中起关键作用。依据 不同个体的 TME, 准确评估和选择临床用药, 可有效控制原位癌和转移癌的恶性转化。目前, 治疗癌症的主要方法 是化疗, 由于 TME 中良性细胞可调节癌细胞对标准化疗和靶向药物治疗的反应, 因此, 结合靶向 TME 治疗会取得更 理想的临床疗效。本文就乳腺癌 TME 中细胞外基质 （ECM）、 肿瘤相关成纤维细胞、 肿瘤相关巨噬细胞、 调节性 T 细 胞和骨髓间质干细胞对肿瘤发生、 发展的作用机制进行综述。