中性粒细胞在肿瘤发生发展及免疫治疗中的作用

中性粒细胞作为机体的重要免疫细胞,在感染、自身免疫性疾病等多种炎症反应中发挥重要作用。然而,中性粒细胞在肿瘤的发生发展过程中也扮演重要角色。一方面,中性粒细胞能够通过杀伤肿瘤细胞发挥抗肿瘤作用;另一方面,中性粒细胞也可以通过分泌多种细胞因子或与其他类型细胞相互作用来促进肿瘤细胞发生免疫逃逸。由于中性粒细胞能够通过多种机制来促进肿瘤的发生发展,因此靶向中性粒细胞的免疫治疗也成为了肿瘤免疫治疗的一个新的思路。本文通过介绍中性粒细胞在肿瘤演进过程中发挥的抗肿瘤效应,促进肿瘤免疫逃逸以及中性粒细胞相关的免疫治疗等方面来阐述中性粒细胞在肿瘤发生发展以及免疫治疗中的重要性。     

肿瘤相关性中性粒细胞促肿瘤转移机制的研究进展

中性粒细胞是循环中最为丰富的白细胞，在机体的免疫反应中发挥重要作用。中性粒细胞不仅参与免疫反应，也在肿瘤的发生发展，特别是侵袭和转移过程中发挥重要作用。中性粒细胞可分化为N1和N2亚型，在肿瘤的转移中表现出抑制转移（N1）和促进转移（N2）两种截然不同的的作用。但肿瘤相关中性粒细胞（tumor-associated neutrophils，TANs）在肿瘤转移机制中发挥的作用相对比较复杂，尚缺乏系统阐述。本文主要介绍TANs，分析其在肿瘤转移过程中促进肿瘤发生侵袭和转移的机制，对TANs作为抗肿瘤治疗策略的可能性进行综述。      

中性粒细胞与肿瘤复杂相关性的研究进展

中性粒细胞具有多重功能,包括分泌趋化因子和细胞因子的能力,形成细胞外陷阱以及对肿瘤增殖与转移进行调控的能力。有关其可塑性与异质性的研究表明,循环中性粒细胞与肿瘤相关中性粒细胞在肿瘤增殖与转移调控中的作用十分显著,并表现为双重作用。一方面,中性粒细胞能够促进肿瘤炎症、肿瘤细胞增殖与侵袭以及肿瘤血管的生成,并且能够通过抑制T细胞的活性,促进肿瘤免疫逃避。另一方面,中性粒细胞能够促进T细胞抗肿瘤效应,并且可以通过产生相应的细胞因子参与肿瘤抑制。此前,肿瘤相关中性粒细胞的研究多以动物模型为依据,近年来,有研究进一步指出了对人类肿瘤相关中性粒细胞的认识,并探讨了中性粒细胞成为肿瘤免疫治疗新靶点的可能性。目前,对于肿瘤与中性粒细胞复杂相关性的多项研究表明,细胞治疗对肿瘤生物学的认识、肿瘤标志物的开发以及肿瘤的治疗均具有重要作用。本文就中性粒细胞与肿瘤复杂相关性研究的进展作一综述。     

G-CSP基因治疗对大剂量化疗后结肠癌小鼠中性粒细胞数量和功能的影响

中性粒细胞作为一种重要效应细胞在机体抗肿瘤过程中发挥重要的作用。为了探讨G-CSF基因治疗及大剂量化疗后对荷瘤小鼠中性粒细胞的影响以及G-CSF基因治疗后中性粒细胞在抗肿瘤中所起的作用,我们对G-CSF基因治疗后荷瘤小鼠中性粒细胞的数量和功能进行了研究。结果发现,G-CSF基因治疗与重组G-CSF(rhG-CSF)注射疗法相比,能更明显地提高结肠癌小鼠中性粒细胞的数量、中性粒细胞的吞噬功能、杀伤C-26细胞的活性以及分泌IL-1、TNF、NO水平。对大剂量化疗后的结肠癌小鼠,仍能明显提高中性粒细胞数量、吞噬功能、杀伤C-26结肠癌细胞的活性以及分泌IL-1、TNF、NO水平。表明G-CSF基因治疗比rhG-CSF注射疗法更有效地纠正并提高由于大剂量化疗后引起的外周血中性粒细胞的降低,增强中性粒细胞的杀伤活性,促进中性粒细胞分泌IL-1等细胞因子,发挥直接或间接的抗肿瘤作用。     

肿瘤相关中性粒细胞的异质性及潜在的临床意义

恶性肿瘤组织中肿瘤相关中性粒细胞（TAN）是肿瘤微环境的重要组成部分。TAN在肿瘤中的作用具有两面性。一方面,TAN可直接杀伤肿瘤细胞,或介导其他免疫细胞协同抗肿瘤。另一方面,TAN也可促进肿瘤血管生成、重塑细胞外基质及参与肿瘤细胞免疫逃逸。以上TAN功能的异质性是其在肿瘤微环境中多种复杂机制的交互调控下形成的,对肿瘤的发展或抑制产生重要的作用。因此,阐明TAN的异质性、不同亚群转化机制及其潜在的临床意义显得尤为重要,不仅有助于开发针对促肿瘤型中性粒细胞亚群的抑制类药物和疗法,还可进一步促进免疫治疗更多获益人群的新评估标准建立和筛选。     

G-CSF基因治疗对大剂量化疗后结肠癌小鼠中性粒细胞数量和功能的影响

中性粒细胞作为一种重要效应细胞在机体抗肿瘤过程中发挥重要的作用。为了探讨G-CSF基因治疗及大剂量化疗后对荷瘤小鼠中性粒细胞的影响以及G-CSF基因治疗后中性粒细胞在抗肿瘤中所起的作用．我们对G-CSF基因治疗后荷瘤小鼠中性粒细胞的数量和功能进行了研究。结果发现．G-CSF基因治疗与重组G-CSF(rhG-CSF)注射疗法相比．能更明显地提高结肠癌小鼠中性粒细胞的数量、中性粒细胞的吞噬功能、杀伤C-26细胞的活性以及分泌IL-1、TNF、NO水平。对大剂量化疗后的结肠癌小鼠．仍能明显提高中性粒细胞数量、吞噬功能、杀伤C-26结肠癌细胞的活性以及分泌IL-l、TNF、NO水平。表明G-CSF基因治疗比rhG-CSF注射疗法更有效地纠正并提高由于大剂量化疗后引起的外周血中性粒细胞的降低．增强中性粒细胞的杀伤活性．促进中性粒细胞分泌IL-1等细胞因子．发挥直接或间接的抗肿瘤作用。     

炎症与免疫指标在可切除性结直肠癌中的预后价值

结直肠癌是世界范围内常见的恶性肿瘤之一,在中国其发病率和病死率逐年增加,年轻化趋势也愈加明显.在肿瘤治疗过程中,免疫及炎症介导的抗肿瘤反应尤为重要,并在肿瘤的发生、发展过程中发挥重要作用.近年来研究发现,中性粒细胞与淋巴细胞比值(neutrophil-lymphocyte ratio,NLR)、血小板与淋巴细胞比值(p...     

未折叠蛋白反应在肿瘤微环境髓样细胞中的功能

大量研究表明肿瘤微环境(tumor microenvironment,TME)中髓样细胞对肿瘤发生发展有着重要作用。髓样细胞主要包括树突状细胞、巨噬细胞、中性粒细胞、髓源性抑制细胞等多种细胞，通过与肿瘤细胞相互作用发挥促癌或抗癌效应。未折叠蛋白反应（unfolded protein response,UPR）是内质网应激(endoplasmic reticulum stress,ERS)下针对未折叠蛋白或错误折叠蛋白而产生的稳态调控，可诱发细胞适应性生存或凋亡。本文主要讨论TME髓样细胞中UPR对肿瘤生长转移的影响，以及靶向干预髓样细胞中UPR各通路在抗肿瘤免疫治疗中的作用。     

中性粒细胞对肺癌血管生成的影响及机制研究

目的：肿瘤相关中性粒细胞在肿瘤的发生发展中发挥重要的作用,但其在肺癌中的作用机制缺乏系统研究,本研究将主要探讨中性粒细胞活化对肺癌血管生成的影响及其分子机制。方法：以人早幼粒白血病细胞系HL-60为基础,利用DMSO诱导其分化为中性粒细胞样细胞,与肺癌细胞共培养活化中性粒细胞,收集中性粒细胞活化上清后进行血管生成实验,应用Realtime-PCR、Western blot和明胶酶谱实验检测血管生成影响因子VEGF和MMP-9的表达情况。结果：中性粒细胞活化产物显著增强肺癌血管生成能力,抑制PARP-1中性粒细胞VEGF和MMP-9表达明显减少,对肺癌血管生成的促进作用受到抑制。结论：PARP-1调控中性粒细胞VEGF和MMP-9表达促进肺癌血管生成。     

肿瘤化疗导致的中性粒细胞减少诊治专家共识（2019年版）

肿瘤化疗导致的中性粒细胞减少是化疗常见的不良反应,其有可能导致化疗药物剂量降低、化疗时间延迟乃至粒细胞减少性发热（febrile neutropenia,FN）和感染,从而增加治疗费用、降低化疗效果和生存质量,影响患者预后。正确评估化疗导致中性粒细胞减少的发生风险,早期识别FN和感染,进行合理的预防和治疗,对提高抗肿瘤治疗整体疗效、降低死亡风险等方面具有重要的意义。基于相关循证医学证据和专家共识,中国抗癌协会肿瘤临床化疗专业委员会和肿瘤支持治疗专业委员会制订了《肿瘤化疗导致的中性粒细胞减少诊治专家共识（2019版）》,旨在为中国肿瘤学医师提供更合理的诊疗方案。      

On the cytokines produced by human neutrophils in tumors

Although traditionally viewed as short-lived innate immunity cells, only playing a crucial role in host defense toward infections, neutrophils have recently become subject of a new wave of research in diverse areas including in tumors. Indeed, increasing experimental evidence indicate that neutrophils may directly or indirectly influence the tumor fate through the release of a wide array of molecules able to exert either pro-tumor or anti-tumor functions depending on the microenvironment milieu, including cytokines. This review therefore attempts to uncover the role that neutrophils play during the different steps of tumor development (from promotion to progression), as well as in anti-tumor responses, via cytokine production.     

Circulating low density neutrophils of breast cancer patients are associated with their worse prognosis due to the impairment of T cell responses

Neutrophils are prominent immune components of tumors, having either anti-tumor (N1) or pro-tumor activity (N2). Circulating neutrophils, divided into high density neutrophils (HDN) and low density neutrophils (LDN), functionally mirror those N1 and N2 cells, respectively. LDN are rare in non-pathological conditions, but frequent in cancer, exhibiting a pro-tumor phenotype. These findings have been mainly demonstrated in animal models, thus proper validation in humans is still imperative. Here, we observed that LDN were increased in the blood of breast cancer (BC) patients, particularly with metastatic disease. Within the population of non-metastatic patients, LDN were more prevalent in patients with poor response to neoadjuvant chemotherapy than patients with a good response. The higher incidence of LDN in BC patients with severe disease or resistance to treatment can be explained by their pro-tumor/immunosuppressive characteristics. Moreover, the percentage of LDN in BC patients’ blood was negatively correlated with activated cytotoxic T lymphocytes and positively correlated with immunosuppressive regulatory T cells. The ability of LDN to spoil anti-tumor immune responses was further demonstrated ex vivo. Hence, this study reveals the potential of LDN as a biomarker of BC response to treatment and opens new avenues for developing new immunotherapies.     

肿瘤相关中性粒细胞与肿瘤的发生和发展

肿瘤微环境中除了肿瘤细胞外,还存在多种类型的其他细胞,包括基质细胞、内皮细胞和各种免疫细胞（如CD4+和CD8+T细胞、树突状细胞、NK细胞、巨噬细胞、中性粒细胞等）。近年来研究发现,肿瘤相关中性粒细胞（tumor-associated neutrophils, TANs）在肿瘤发生和发展中发挥着重要的作用。TANs可以通过多种机制促进肿瘤的生长和转移,这些机制包括TANs释放的弹性蛋白酶促进肿瘤增殖和转移,TANs分泌基质金属蛋白酶促进肿瘤血管的生成,同时高度活化的TANs也可杀伤肿瘤细胞起抗肿瘤的作用。对TANs的深入研究为肿瘤免疫提供了新的认识,以TANs及其分泌的一些分子作为靶点来调控TANs的功能,可能成为干预肿瘤发生、发展的重要方法。     

bufalin调控信号转导通路抗肿瘤机制的研究进展

中药是祖国医学的瑰宝,在我国,中成药或多或少的应用在癌症患者治疗的不同阶段,但是有部分医生或患者对中药的作用持保留态度,限制了中药的推广和应用。华蟾素具有抗肿瘤、抗病毒、强心、增强免疫力、止痛、麻醉、诱导血管收缩等作用,在恶性肿瘤治疗中应用广泛。其中bufalin是其发挥功能的重要单体,而部分医生对其抗肿瘤机制并不熟悉,本文拟对bufalin的抗肿瘤机制作出综述,为其临床应用提供理论依据。     

Anti-tumor Effects of Hyperthermia Plus Granulocyte Colony-stimulating Factor

The role of neutrophils in the anti-tumor effects of hyperthermia was investigated in an experimental rat model, and the efficacy of hyperthermia combined with recombinant human granulocyte colony-stimulating factor (G-CSF) was similarly investigated. AH109A carcinoma cells were transplanted into the hind legs of Donryu rats, then heated by a radio-frequency dielectric heater. In this study, because the myeloperoxidase (MPO) activity of neutrophils was not affected by heating or G-CSF, MPO activity was measured as an index of neutrophil migration into tumor tissue. After hyperthermia, MFO activity in tumor tissue increased significantly, suggesting migration of neutrophils into tumor tissue. Depletion of circulating neutrophils by the intraperitoneal injection of anti-rat neutrophil antibody decreased the anti-tumor effects of hyperthermia. Subsequently, we used hyperthermia plus intraarterial G-CSF to enhance the anti-tumor effect. Hyperthermia was induced 1 h after injection of G-CSF, a time when MPO activity in tumor tissue was maximal. A satisfactory thermal effect was noted even in cases where tissue could not be heated sufficiently. In conclusion, neutrophils have an important role in the anti-tumor effects of hyperthermia, and administration of G-CSF enhances these effects.     

Correlation between the sensitivity or resistance to IL-2 and the response to cyclophosphamide of 4 tumors transplantable in the same murine host

We have studied the anti-tumor response to cyclophosphamide (CTX) in DBA/2 mice transplanted s.c. with 4 tumors exhibiting different responses to IL-2: ESb lymphoma and Friend leukemia cells (non-responsive or poorly responsive, respectively), pI I-R-Eb and Eb lymphoma cells (both highly responsive to IL-2). CTX injections on days 7, 14 and 21 resulted in a significant anti-tumor response in mice transplanted s.c. with Friend leukemia cells or ESb cells, whereas no anti-tumor effect was observed in mice injected with Eb or pI I-R-Eb cells. All 4 tumor cell lines were equally sensitive to the cytotoxic effects of mafosfamide, an in vitro active analogue of CTX. To define the host mechanisms responsible for the lack of an anti-tumor effect of CTX in mice transplanted with IL-2-responsive tumors, we studied several aspects of the spontaneous or IL-2-induced anti-tumor response in mice transplanted with pI I-R-Eb cells. Injection of monoclonal antibodies (MAbs) to IFN-γ completely abolished the anti-tumor effects of IL-2. Using a Winn assay, clear-cut anti-tumor activity was found in spleen cells from mice transplanted with the IL-2-responsive tumors. This activity was abolished by CTX, which also abrogated the anti-tumor response to IL-2 in mice injected with pI I-R-Eb cells. Our results indicate an inverse correlation between sensitivity to IL-2 and response to CTX and emphasize the importance of initial host-tumor interaction in determining the type of response to IL-2 or CTX. © 1995 Wiley-Liss, Inc.     

肿瘤囊泡：通向肿瘤免疫生物治疗之路

在发生凋亡和受到信号刺激时,细胞会释放直径为0.1~1 μm的膜状囊泡,这样的膜状囊泡称之为微颗粒。其释放受到细胞骨架和生物机械力的影响,在正常细胞和恶性肿瘤细胞中起着传递信息的作用。最近笔者实验室通过肿瘤细胞来源的囊泡研发出一套新型的天然载药系统,其可以有效地将药物输送到肿瘤干细胞的细胞核,进而有效杀伤肿瘤干细胞而不产生副作用。其潜在的机制涉及肿瘤干细胞的柔软特性可以更好地摄取囊泡,载药囊泡进入溶酶体并促进溶酶体向细胞核运动进而将药物输送至细胞核。肿瘤细胞来源的载药囊泡已经进入临床试验,用于治疗梗阻性肿瘤和肿瘤导致的恶性积液。此外,肿瘤细胞来源的囊泡可以有效地被DC摄取,通过改变肿瘤细胞溶酶体的pH值以及激活DC的cGAS/STING通路产生Ⅰ型干扰素,进而促进DC对肿瘤细胞的抗原提呈,因而肿瘤细胞来源的囊泡可以作为理想的抗肿瘤疫苗。总之,肿瘤细胞来源的囊泡在今后的肿瘤免疫生物治疗和预防中有着广泛的应用前景。