鼻咽癌肿瘤微环境研究进展[综述]

鼻咽癌具有起病隐匿、转移早、易复发的特点,治疗主要以放化疗为主,但对晚期患者效果欠佳。诸多研究表明肿瘤微环境可促进机体形成免疫抑制,避免肿瘤细胞遭受药物渗透,帮助肿瘤细胞逃避免疫攻击,从而促进肿瘤发展。鼻咽癌肿瘤微环境中浸润有大量免疫细胞和免疫因子,能够帮助肿瘤细胞完成免疫逃逸。本文旨在对鼻咽癌肿瘤微环境研究进展做一综述,为其研究与应用提供理论依据。     

鼻咽癌肿瘤微环境研究进展

鼻咽癌具有起病隐匿、转移早、易复发的特点, 治疗主要以放化疗为主, 但对晚期患者效果欠佳。诸多研究表明肿瘤微环境可促进机体形成免疫抑制, 避免肿瘤细胞遭受药物渗透, 帮助肿瘤细胞逃避免疫攻击, 从而促进肿瘤发展。鼻咽癌肿瘤微环境中浸润有大量免疫细胞和免疫因子, 能够帮助肿瘤细胞完成免疫逃逸。本文旨在对鼻咽癌肿瘤微环境研究进展做一综述, 为其研究与应用提供理论依据。     

肿瘤免疫抑制因子与头颈部肿瘤

在肿瘤发病的诸多因素中,各种类型的免疫抑制因子使肿瘤局部成为一个深度的免疫抑制区,它们作为肿瘤免疫逃逸的发生机制之一,在肿瘤的形成及发展过程中起着关键作用。目前已知,许多头颈部肿瘤微环境中均存在不同种类的免疫抑制因子,它们在肿瘤细胞中的表达及在患者体液中的含量变化可望成为辅助判断疗效、观察预后的临床监测指标,为临床最佳治疗方案的选择提供理论依据,并可作为抗瘤药物的新靶点,为头颈部肿瘤的生物治疗提供新思路。     

肿瘤微环境乏氧和相关基因研究进展

微环境乏氧在肿瘤侵袭、转移和对放化疗抵抗方面发挥着重要作用.根据其形成机制不同,大体分为急性乏氧和慢性乏氧,二者对肿瘤细胞的影响具有很大的相似性,但又不完全相同.肿瘤微环境乏氧的存在使得肿瘤细胞一系列基因转录活性发生改变,其表达产物一方面对肿瘤细胞起到一定的保护作用,促其适应乏氧微环境;另一方面又对肿瘤生长、能量代谢、血管生成、转移和凋亡产生不良影响,造成肿瘤细胞侵袭力增强、凋亡下降、对放化疗抵抗.因此,针对肿瘤微环境乏氧和相关基因进行研究将会为肿瘤治疗带来新的曙光.     

头颈部鳞状细胞癌免疫治疗研究进展

头颈部鳞状细胞癌(鳞癌)作为一种免疫抑制性肿瘤,免疫逃逸及T细胞信号的破坏是其发生发展的重要机制,免疫治疗以此为靶点通过其独特的作用机制在头颈部鳞癌的治疗中成为了又一重要的治疗手段。在临床治疗中,若想达到理想的治疗效果,需要采取多学科联合治疗。其中,免疫治疗可与其他治疗手段联合或者不同的免疫治疗相结合,从而达到更好的治疗效果。本文就肿瘤免疫微环境的改变及当前头颈部鳞癌免疫治疗研究进展作一系统综述,以期更好地指导临床治疗。     

安罗替尼联合治疗在肿瘤治疗中的研究进展

安罗替尼是一种多靶点酪氨酸激酶抑制剂,可以通过调节肿瘤内血管的生成或改变免疫抑制微环境,发挥其抗肿瘤作用。安罗替尼已批准应用于非小细胞肺癌、软组织肉瘤、小细胞肺癌等多种类型肿瘤的临床治疗,并且在部分晚期或复发的患者取得一定治疗效果。多项临床研究发现安罗替尼与化疗、放疗、免疫检查点抑制剂等联合治疗可以显著抑制肿瘤,其治疗效果明显优于安罗替尼单药应用。论文对安罗替尼的作用机制及其在肿瘤中的联合治疗研究进展进行综述。     

2型神经纤维瘤病相关前庭神经鞘瘤肿瘤微环境研究进展

2型神经纤维瘤病（neurofibromatosis type 2, NF2）是一种少见的常染色体显性遗传疾病。NF2基因定位于22q12.2染色体的抑癌基因,由于该基因发生突变引起的全身性多发肿瘤综合征。双侧前庭神经鞘瘤（bilateral vestibular schwannoma,BVS）是NF2的最显著特征。较散发性的前庭神经鞘瘤（vestibule schwannoma,VS）相比,术中观察NF2-BVS血供比较丰富,并且NF2肿瘤易复发,类似于低度恶性肿瘤。所以NF2-BVS与散发的VS是否是相同肿瘤有待进一步探索。NF2-BVS多以手术治疗为主,患者大多要面临多次手术的情况,并且术后多伴有听力减退等并发症,治疗效果及生存质量远不及散发性VS。随着对于肿瘤微环境（tumor microenvironment,TME）及肿瘤相关巨噬细胞（tumor associated macrophages,TAMs）促进肿瘤生长方面研究的深入。基于TME的针对NF2-BVS的新型治疗方法探索十分有必要。文章概述NF2-BVS疾病的特点及目前治疗手段的不足,肿瘤相关巨噬细胞对于肿瘤生长的促...     

细胞外囊泡在头颈部肿瘤中的研究进展

肿瘤的增殖和转移能力是由肿瘤微环境(TME)中细胞间的“相互对话”介导的。细胞外囊泡(EVs)是细胞主动分泌、可以介导细胞间通信的一种囊泡状小体,几乎来自所有类型的细胞,是癌细胞及其微环境之间的关键信号介质,在实现TME细胞间物质转运和信息传递方面发挥着重要作用。肿瘤细胞来源的EVs可以通过激活多种信号通路改变靶细胞生理状态,影响肿瘤微环境等方式参与肿瘤细胞的增殖与迁移。EVs在头颈部肿瘤(HNCs)中的分子机制和临床应用尚处于早期阶段,有待进一步研究。以头颈肿瘤的TME为研究重心,阐明EVs复杂的信号网络参与介导肿瘤增殖、侵袭转移、血管生成和肿瘤耐药的相关机制。     

头颈部肿瘤炎性微环境的研究进展

头颈部肿瘤由于解剖学特点,易出现感染和炎症反应。近年来研究发现由炎性细胞和复杂的促炎因子网络组成的炎性微环境在头颈部肿瘤的发生、发展过程中起重要作用。本文旨在针对头颈部肿瘤的炎性微环境在肿瘤发生、发展过程中所起的重要作用进行综述。     

头颈鳞状细胞癌乏氧微环境与放疗抵抗相关性的研究进展

头颈鳞状细胞癌(HNSCC)的治疗方式有手术和放化疗.治疗后HSNCC的高复发率及其显著的转移能力是影响HNSCC患者预后的主要因素,且放化疗存在各种并发症,包括放射性口腔黏膜炎、局部软组织损伤等,严重影响患者生活质量.而肿瘤局部组织内乏氧造成的乏氧微环境与肿瘤治疗抵抗和复发的关系密切相关,如果能采取措施改善肿瘤微环境...     

肿瘤相关巨噬细胞和基质溶解素在喉鳞状细胞癌组织的表达与肿瘤微血管密度的关系

目的：探讨CD68抗体标记的肿瘤相关巨噬细胞TAMs和基质溶解素MMP-7在喉鳞状细胞癌组织的表达及与临床病理参数的关系,探讨两种分子标志物表达与喉癌组织MVD的关系。方法：使用免疫组织化学法检测标本65例（喉鳞状细胞癌组织45例,瘤旁非肿瘤组织20例）中CD68及MMP-7、CD34抗体标记的MVD的表达。结果：CD68阳性表达率,鳞癌组织（82.2%,37/45）与瘤旁组织（15.0%,3/20）比较,差异有统计学意义（P〈0.05）。MMP-7阳性率鳞癌组织（71.1%,32/45）与瘤旁组织（25.0%,5/20）比较,差异有统计学意义（P〈0.05）。CD34-MVD鳞癌组织（26.52±6.36）高于瘤旁组织（12.23±4.01）。有淋巴结转移组CD68、MMP-7阳性率高于无淋巴结转移组;MMP-7、CD68表达与分化程度无关;MMP-7与肿瘤分期无关,而CD68与肿瘤分期相关;CD68、MMP-7与CD34-MVD有正相关性。结论：两种分子标志物在喉癌组织的高表达及与MVD的正相关性说明了TAMs与MMP-7在促进喉鳞状细胞癌组织的转移及新生血管形成中发挥了作用,可作为判断喉癌侵袭及转移的重要标志物。     

The clinical implications of antitumor immunity in head and neck cancer

Recent developments have renewed interest in understanding the interaction between transformed cells and the immune system in the tumor microenvironment. Here, we provide a comprehensive review addressing the basics of tumor immunology in relation to head and neck cancer and the cellular components potentially involved in antitumor immune responses. In addition, we describe the mechanisms by which head and neck cancer cells escape immune-mediated killing and progress to form clinically significant disease. Further, we detail what effects standard anticancer therapies may have on antitumor immune responses and how these responses may be altered by current and investigational immunotherapies. Finally, we discuss future directions that need to be considered in the development of new immunotherapeutics designed to durably alter the immune response in favor of the host.     

头颈部恶性肿瘤类器官研究现状及应用

在精准医疗时代,头颈恶性肿瘤类器官培养技术能够维持肿瘤细胞的高度异质性,更好地模拟体内的肿瘤微环境,培养效率高、耗时少,同时具备肿瘤细胞系可进行遗传操作的优点和小鼠PDX模型的三维复杂系统特性,可作为测试肿瘤药物和个体化肿瘤疗法的新型平台,利于致癌基因建模、靶基因发现和个体化药物敏感性检测,可用于头颈恶性肿瘤的精准治疗...     

Induction of antitumor immune response in the mouse model after vaccination with B7.1 expressing tumor cells

The aim of the study was the induction of an antitumor immune response by genetic modification of tumor cells. This was done by transfecting the costimulatory molecule B7.1 into a murine tumor cell line SCCVII/SF in order to increase T cell recognition and to install an immunologic memory. One cohort of immunocompetent mice C3 H/HeN were injected with B7.1 expressing tumor cells, while the control group received parental B7.1 negative tumor cells. In a second step those immunized mice were rechallenged by parental tumor cells and tumor growth was compared to a new control group. Transfection with B7.1 prohibits outgrowth of the SCCVII cell line. Animals that have been vaccinated in this way are partially immune towards a secondary exposition to B7.1 negative tumor cells. Outgrowth of this recurrent tumor is slowed down. Such an immunization builds up an immunologic memory. Vaccination with B7.1 expressing tumor cells lead to a partial protective tumor immunity in the SCCVII-C3 H/HeN mouse model.     

Regulatorische T-Zellen und NK-Zellen bei Krebspatienten

NK cells represent the cells of the immune system most effective for eradication of infected or neoplastic cells. Regulatory T cells and the two main subgroups thereof—the naturally occurring nTregs and the tumor-associated induced Tregs (iTregs)—play an important role in the antitumor immune response in cancer patients. The current study explores the intercellular interactions of these groups of cells in tumor patients, particularly in head and neck cancer. Critical interactions between these cells and the cancer cells could be observed in extensive experimental analyses. Firstly, we generated tumor-associated iTregs in a specific human culture. Subsequently, various phenotypic and functional relationships between these cells, nTregs, NK cells and tumor cells were analyzed in an autologous system. Although the activity of naive NK cells was enhanced by iTregs in the presence of tumor cells, the cytotoxic function of NK cells activated by interleukin-2 was markedly inhibited by iTregs and nTregs. Our group was able to document new insights into the complex regulation of human NK cells and regulatory T cells in the tumor microenvironment. These new insights may be of relevance for an improved understanding of the antitumor immune response and the development of immunotherapeutic strategies.     

A case of Kuttner tumor of the submandibular gland

Kuttner tumor (known as chronic sclerosing sialadenitis) is a totally benign inflammatory lesion and to date there has been no report of malignancy. However, because of its clinical features, the clinical diagnosis is often that of a salivary gland neoplasm. We report a case of Kuttner tumor and discuss its differential diagnosis, especially the pathological diagnosis. Kuttner tumor may be mainly due to T lymphocyte immune reaction and of itself is a benign lesion, but it may provide a state in which a malignant lesion arises.     

Extracellular matrix metalloprotease inducer stimulates fibroblast-mediated tumor growth in vivo

HYPOTHESIS: Extracellular matrix metalloprotease inducer (EMMPRIN) is a molecule expressed on the cell surface of tumor cells that has been shown to induce both tumor cells and fibroblasts to express matrix metalloproteases in vitro. We hypothesize that fibroblasts are stimulated by EMMPRIN to create a microenvironment favorable to tumor growth. STUDY DESIGN: Case series review of laryngeal cancer and assessment of tumor cell lines in vivo. METHODS: EMMPRIN immunoreactivity in 33 pathologic specimens from patients with supraglottic laryngeal cancer was correlated with clinicopathologic features and survival. The CAL 27 cell line was transfected with EMMPRIN (CAL 27E) or a control vector (CAL 27). Cells were xenografted into the flank of severe combined immunodeficient (SCID) mice with or without a co-injection of normal dermal fibroblasts (NDFs). RESULTS: Immunohistochemical detection of EMMPRIN in laryngeal cancer specimens demonstrated expression in all the tumors but not in adjacent, histologically normal mucosa. EMMPRIN membrane immunoreactivity (transmembrane EMMPRIN score) was associated with nodal positivity (P=.07), and it was associated with poorer survival (hazard ratio=2.4, 95% confidence interval 0.88, 6.55). As a categoric variable, higher EMMPRIN expression positively correlates with higher mortality. To determine whether EMMPRIN mediates tumor growth in vivo through fibroblast stimulation, EMMPRIN-expressing CAL 27 (CAL 27E) xenografted (n=20) onto the flank of SCID mice developed larger tumors than CAL 27 control vector transfected cells alone (n=20), but they were not significantly larger (P=.17). However, when CAL 27E cells were co-injected with NDFs, there was a statistically significant increase in tumor growth compared with the CAL 27 cells co-injected with NDFs (n=10, P=.0038). CONCLUSIONS: As a cell surface expressed protein that promotes tumor growth and high expression in head and neck squamous cell carcinoma but not in normal tissue, EMMPRIN may be a good target for directed molecular therapy.     

The presence of tumor-infiltrating IL-17-producing cells in juvenile nasopharyngeal angiofibroma tumor microenvironment is a poor prognostic factor

Background

Although juvenile nasopharyngeal angiofibroma (JNA) is a benign tumor histologically, it demonstrates aggressive propensity of locally destructive growth causing bone erosion. The patients with JNA remain high recurrence rate after surgical excision. Th17 cells secrete the proinflammatory cytokine interleukin-17 (IL-17), and play an important role in carcinogenesis and tumor progression. So far, no studies have focused on the significance of IL-17-producing cells in the JNA tumor microenvironment. The current study was designed to investigate the localization and level of tumor-infiltrating IL-17-producing cells in JNA microenvironment. The presence and number of IL-17-producing cells were further analyzed for a possible association with clinicopathological features and disease outcome.

Materials and methods

Immunohistochemistry was used to analyze the expression of IL-17 in a tissue microarray from 70 patients with JNA and 10 control subjects. Correlations between the levels of IL-17 expression and clinicopathologic variables, as well as tumor recurrence, were assessed.

Results

In vessels, the IL-17-producing cells were identified in pericytes and irregular smooth muscle cells, but the matured vascular endothelial cells showed no IL-17 reactivity. The expression of IL-17 in stromal cells was concentrated in the less differentiated and plump cells that contained a central hypochromatic nucleus and single small nucleolus. Chi-square test showed that tumor stage (p = 0.09), operation history (p = 0.828), operation approach (p = 0.159), and volume of intraoperative hemorrhage (p = 0.352) were not associated with the expression of IL-17 in JNA patients. However, intratumoral IL-17-producing cells were negatively associated with patient's age (p = 0.004). Furthermore, we found that patients with extensive infiltration of IL-17-producing cells had significantly higher recurrence rates than those with less infiltration of IL-17-producing cells (p = 0.028). Log rank analysis showed that JNA patients with high levels of IL-17 had significantly shorter disease free survival (DFS) than those with low levels of IL-17 (p = 0.004). Univariate Cox regression analysis suggested that IL-17 and patient's age were significantly associated with DFS. Multivariate analysis indicated that high infiltration with IL-17-producing cells was associated with poor DFS. Of all clinicopathological features, IL-17 level was an independent factor predicting the patient's prognosis.

Conclusion

In JNA patients, a high level of IL-17-producing cells was negatively associated with patient's age. Patients with extensive infiltration of IL-17-producing cells had significantly higher tumor recurrence rates. High infiltration of IL-17-producing cells in JNA microenvironment is an independent poor prognostic factor for shorter disease-free survival. Future studies further focusing on the role of IL-17 may provide more promising therapeutic methods for extensive JNA tumors.     

Assessment of expression of toll-like receptors 2, 3 and 4 in laryngeal carcinoma

Head and neck cancers remain a big challenge for oncology. Among them laryngeal carcinomas predominate. In spite of abundant inflammatory cell infiltrates containing several immunologically competent cells, patients with head and neck cancers show markedly suppressed anti-tumor response. In general, cancer cells use strategies to avoid recognition and destruction by the immune system. Toll-like receptors 1–13 (TLRs) are crucial for activation of innate immunity and secondarily for the induction of acquired response. TLRs are mainly expressed on cells of the immune system, but they have been demonstrated on endothelial and epithelial cells. Ligand binding to TLR leads to the activation of several genes, predominantly proinflammatory ones such as IL-1 and TNF-alpha and maturation of professional antigen presenting cells (APC) i.e., dendritic cells. It can cause better tumor antigen presentation by APC. The aim of this study was the evaluation of expression of TLR-2, TLR-3 and TLR-4 in the microenvironment of laryngeal carcinoma. Tumor specimens (n = 20, male patients aged 43–77 years, mean 57 years) from patients subjected to total laryngectomy. Immunohistochemistry and indirect immunoflourescence on frozen tissue sections. Cancer tissue: portion of cancer cells manifested membrane and/or cytoplasmic expression of TLR-2, TLR-3 and TLR-4. The most frequent expression on tumor cells was TLR-2 and the least expression of TLR-4. Inflammatory infiltrates: in all cases inflammatory cell infiltrates of various intensities were present, both in tumor mass and tumor stroma. Expression of all TLRs tested, both, membrane and cytoplasmic ones were shown on inflammatory cells, but distinct in quantitative terms. TLR-4 positive cells were the most frequent. A portion of cells expressed both, TLR and HLA-DR. It is of interest that TLRs tested were expressed not only on cells of inflammatory infiltrate, but also on tumor cells. This fact may be an important factor in tumor escape from immune surveillance. It is notable, that both, TLRs and HLA-DR were shown to be co-expressed, what may favor the role and impact of TLRs in antigen presentation. Further studies are needed to elucidate TLRs function in the course of neoplastic process.