• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Crosstalk between cancer cell plasticity and immune microenvironment in cholangiocarcinoma

    2024-06-08 18:41:57MirkoMininiAllanPavyBouchraLekbabyLauraFouassier
    Hepatoma Research 2024年1期

    Mirko Minini, Allan Pavy, Bouchra Lekbaby, Laura Fouassier,2

    1Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, Paris 75571, France.

    2Association pour l'étude des Cancers et Affections des voies Biliaires (ACABi), Saint-Cloud 92210, France.

    Abstract Cholangiocarcinoma (CCA) is a highly aggressive tumor of the biliary tree characterized by an intense desmoplastic tumor microenvironment (TME).To date, treatment of CCA remains challenging; tumor resection is the only curative treatment with a high recurrence probability.Besides resection, therapeutic options have moved forward with the advent of immunotherapies, but these remain limited and low effective.Our knowledge about the cellular interplays in CCA is still fragmentary.An area is currently emerging regarding the potential role of cancer cell plasticity in the genesis of an immunosuppressive microenvironment.The cancer cells’ ability to acquire stemness properties and to disseminate through an epithelial-mesenchymal transition (EMT) shape a tumor immune microenvironment that supports cancer progression by attracting immunosuppressive cells including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), M2 macrophages, and by increasing the expression of inhibitory immune checkpoints such as PD-1/PD-L-1.EMT-inducing transcription factors (EMT-TF)have recently emerged as regulators of tumor immunity by creating an immunosuppressive microenvironment.This review delves into the molecular mechanisms underlying the existing links between EMT/stemness and tumor immune microenvironment, as well as the last discoveries in CCA.

    Keywords: Cancer cell plasticity, epithelial-mesenchymal transition, cancer stem cells, EMT-TF, immune evasion

    INTRODUCTION

    The great adaptability of cancer cells in nature confers cellular plasticity and heterogeneity inside the tumor[1].Cell plasticity in cancer is an adaptive mechanism irrespective of genetic alterations by which cancer cells modify their phenotype in response to external cues.Owing to cellular plasticity, cancer cells acquire pro-invasive capabilities and stem cell properties, stimulate an immunosuppressive microenvironment, and resist anti-cancer treatments.The best-known plasticity process is the EMT, which prompts cells to transition from an epithelial phenotype to a mesenchymal one, contributing to tumor progression and dissemination[2].Cells undergoing EMT can also acquire stemness traits favoring tumor persistence and drug resistance.Indeed, EMT is also considered a defense mechanism that endows cancer cells with an advantage in proliferation, motility, and resistance to drugs, including immunotherapies.Beyond current knowledge on cell plasticity, recent studies strongly indicate that this ability enables cancer cells to escape the immune system through mechanisms that start to be elucidated.Through cell plasticity,tumor cells contribute to the establishment of an immunosuppressive TME, limiting the immune control of the tumor[3].The interconnection between cell plasticity and immune evasion involves signals from cancer cells, and from both cellular and acellular components of TME.Among these signals, intracellular and extracellular factors already identified as major regulators of EMT and stemness contribute to abolishing the anti-immune response.Soluble factors such as the prototypal cytokine-induced EMT, transforming growth factor-β1 (TGF-β1), EMT-inducing transcription factors (EMT-TFs) including zinc finger E-box binding homeobox 1/2 (ZEB1/2), Snail family transcriptional repressor 1/2 (SNAI1/2) and TWIST family bHLH transcription factor 1/2 (TWIST 1/2), and epigenetic factors have been involved in the regulation of immune response in several carcinomas by remodeling the TME.The purpose of this review is to provide an overview of two major pathophysiological processes that are obviously intertwined in cancer, i.e., cell plasticity and immunobiology.

    EPITHELIAL-MESENCHYMAL TRANSITION AND TUMOR IMMUNE MICROENVIRONMENT

    EMT is a multi-step cellular plasticity program essential for embryonic development and organogenesis,which is also critical for cancer initiation, progression, and metastasis[4].During EMT, epithelial cancer cells progressively lose their apico-basal polarity and cell junctions to acquire mesenchymal cell traits characterized by the expression of extracellular matrix (ECM) remodeling components and higher motility.All these events endow the cancer cells with spread properties into the adjacent tissue and distance into secondary tissues.As a dynamic reversible process, EMT generates a continuum of cells with intermediate,hybrid epithelial, and mesenchymal phenotypes.Cancer cell plasticity through EMT shapes a tumor immune microenvironment favorable to cancer progression by attracting immunosuppressive cells including myeloid-derived suppressor cells (MDSC), Tregs, M2 macrophages, and by increasing the expression of inhibitory immune checkpoints such as PD-1/PD-L-1.Correlative immunohistochemical analyses of EMT and immune markers in a large diversity of human solid cancers are in favor of an interplay between cell plasticity and immunosuppressive TME.In lung adenocarcinomas that display an EMT phenotype, the mesenchymal status of the tumor cells correlates with an increased expression of immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, B7-H3 (CD276), BTLA and CTLA-4[5].Similarly, the expression of the metalloproteinase MMP-13 and TWIST1, two EMT markers, is associated with the expression of CTLA-4/PD-1/PD-L1/TIM-3/LAG-3 in esophageal squamous cell carcinoma[6].In ovarian, prostate, and lung cancers, EMT signature correlates with a higher expression of immune checkpoint proteins, increased infiltration of immunosuppressive cells Tregs and M2 macrophages, and a lower CD8+T cells infiltration[5,7-9].A pan-cancer EMT analysis of The Cancer Genome Atlas (TCGA) dataset has evidenced that EMT-high tumors (mesenchymal-like) have a higher immunosuppressive TME compared to EMT-low (epithelial-like) tumors[7].EMT-high tumors are distinguished by the infiltration of tumor-associated macrophages (TAM), the overexpression of immune checkpoint molecules, the upregulation of immune inhibitory cytokines TGF-β1 and IL10, and the enrichment of inflammatory and exhausted CD8+T-cell signatures[10,11].Similar results were found in colorectal cancer (CRC).In conclusion, according to several cancer analyses from public and non-public datasets, there is a positive interdependence between the EMT status of a tumor and its immunosuppressive nature.This correlative statement may serve to identify potential biomarkers and to stratify patients for personalized treatments with immune checkpoint inhibitors or other immunotherapy approaches.

    Mechanistically, EMT is governed by a panel of transcription factors (i.e., EMT-TF) that regulate the expression of epithelial and mesenchymal markers, in negative and positive ways, respectively.The most known EMT-TFs include SNAl1/2, ZEB1/2, and TWIST1/2.Besides transcription factors, tumor cells produce many different soluble autocrine and paracrine factors that trigger EMT directly or indirectlyviathe stromal (CAF) or immune cells[12].For instance, TGF-β1 is a pleiotropic cytokine with multiple biological effects in cancer, either an antitumoral role in the early stages of carcinogenesis, or a pro-tumoral function in later stages.In the latter case, the cytokine is by far a well-known EMT inducer produced by both tumor and TME cells[12].TGF-β1 signaling drives tumor cell plasticity by inducing mesenchymal features along with stemness traits, leading to cell invasion and resistance to anti-cancer drugs.In addition,TGF-β1 shapes an immune-suppressive TME by upregulating the expression of immune checkpoints and attracting immunosuppressive cells.TGF-β1 may also affect immune surveillance by decreasing immunoproteasome, which is a process generating peptides binding to HLA I molecules to facilitate antigen presentation to CD8+T cells[13].Extracellular cues emerging from acellular components of TME also regulate EMT.Indeed, ECM molecules or ECM remodeling proteins activate intracellular signaling pathways followed by EMT-TF activation to drive EMT[12].The underlying molecular mechanisms at the origin of the interplay between EMT and immunosuppression have partly been identified.SNAI1, ZEB1, and TWIST1 are transcription factors governing EMT that also regulate antitumor immune responses.Beyond the regulation of the expression of epithelial and mesenchymal markers, these transcription factors regulate the expression of inhibitory immune checkpoints and soluble factors that attract immunosuppressive cells[14].A summary of these regulations is provided in the next chapter.

    REGULATION OF TUMOR IMMUNE MICROENVIRONMENT BY EPITHELIALMESENCHYMAL TRANSITION-INDUCING TRANSCRIPTION FACTORS

    SNAI1

    SNAI1 regulates the expression of thrombospondin 1 (TSP1) in melanoma cells, which is a secreted matrix protein that promotes Tregs infiltration and impairs dendritic cell (DC) functions[15].Cancer cells expressing SNAI1 release chemokine ligand 2 (CCL2)/monocyte chemoattractant protein 1, (MCP1) and lipocalin 2(LCN2).Together, CCL2 and lipocalin 2 stimulate regulatory dendritic cells (DCreg), which display an immunosuppressive activity, by decreasing the expression of costimulatory molecules (e.g., HLA-DR) and increasing the expression of immunosuppressive molecules (e.g., PD-L1) in human peripheral blood mononuclear cells (PBMCs).The CCL2/LCN2-induced DCreg cells subsequently trigger the proliferation of immunosuppressive CD4+/FOXP3+Treg cells and impair tumor-specific cytosolic T cells (CTL)induction[16].In breast cancer cells, SNAI1 induces mesenchymal and stemness features that alter the susceptibility of cancer cells to T-cell-mediated immune surveillance through an autophagy mechanism[17].Additionally, SNAI1 stimulates the expression of PD-L1 at the surface of breast cancer cellsviaa posttranslational upregulation of proteins containing the CKLF-like MARVEL transmembrane (CMTM) 6 and 7, leading to immune evasion[18].In the transgenic MMTV-PyMT mouse model of breast adenocarcinoma,SNAI1highmesenchymal cancer cells exhibited an increased Tregs infiltration and a M2 macrophage polarization compared to SNAI1lowepithelial cancer cells and displayed high resistance to anti-CTLA-4 treatment[19].Overexpression of SNAI1 or ZEB1 in breast cancer cells leads to an increased expression of CD47, a macrophage immune checkpoint protein also considered as a “don’t eat me” signal that suppresses macrophage phagocytic activity, preventing cancer cell death from macrophages.It has been shown that both transcription factors SNAI1 and ZEB1 directly bind to two E-boxes located on theCD47gene promoter.The analysis of ChIP-seq data performed in mice breast tumors showed that SNAI1 can bind to many more genes; 89 immunomodulatory genes were identified, including the promoters ofNt5e(coding CD73),Csf1andSpp1genes[20].SNAI1 regulates the expression of other immunosuppressive factors including CXCL1 and CXCL2, two chemokines that attract the immunosuppressive cells MDSCs to the tumorviaCXCR2[21].Post-translational modification of SNAI1 by CREB-binding protein (CBP) prevents the repressor complex formation and induces the transcription ofTNFA,CCL2, andCCL5, promoting the recruitment of TAM and tumor progression[22].In humans, analysis of TCGA and METABRIC data sets from breast cancer patients highlighted a correlation between CD47, SNAI1, and vimentin[23].

    ZEB1

    In breast cancer and non-small-cell lung cancer (NSCLC) cells, ZEB1 upregulates PD-L1 expression by downregulating miR-200, a well-known repressor of PD-L1 expression[11].By indirectly upregulating PD-L1,ZEB1 leads to the exhaustion of CD8+T cells[11].However, ZEB1 has been shown to directly regulate PD-L1 expression by binding its gene promoter that contains a ZEB1 binding E-box[24].In colorectal cancer,expression of ZEB1 positively correlates with PD-L1[25].In patients, co-expression of ZEB1 and PD-L1 is associated with a higher cervical lymph node metastasis and a lower survival rate in oral squamous cell carcinoma[26].ZEB1 also induces the expression of CD47 in cancer-invading cells (i.e., mesenchymal-like cells), driving the M2 polarization of adjacent TAMs in the lung adenocarcinoma mouse model.Thus, ZEB1 reprograms the immune microenvironment surrounding invading clusters[24].ZEB1 impacts CD70 expression in lung cancer mesenchymal cell lines; CD70 belongs to the tumor necrosis factor (TNF)superfamily, and its expression in T cells limits their expansion.In mesenchymal NSCLC patient samples,CD70 is overexpressed and positively associated with decreased CD3+and CD8+T-cell infiltration and increased T-cell exhaustion markers[27].Recently, Caramel and Coll.have nicely demonstrated that ZEB1 expression in melanoma cells is associated with a decreased CD8+T-cell infiltration.They show that ZEB1 directly represses the secretion of T cell-attracting chemokines, including CXCL10, leading to resistance against immune checkpoint inhibitors[28].

    TWIST1

    TWIST1 has been shown to regulate CSF1 (Colony-stimulating factor-1/MCSF), a TAM chemotactic molecule, through a transcriptional regulation since CSF1 promotor contains TWIST responsive elements[29].Biologically, TWIST1 increases the expression of CSF1, inducing an activation and polarization of TAM[29].In addition to CSF1, TWIST1 regulates CCL2 in human mammary epithelial cells, promoting the attraction of macrophagesin vitroand their infiltrationin vivo[30].In a murine model of MYC-driven hepatocellular carcinoma (HCC), TWIST1 cooperates with MYC to induce a transcriptional program that stimulates the expression of CCL2 and IL13, leading to the recruitment and polarization of TAM[31].

    In conclusion, several EMT-TFs directly or indirectly initiate transcriptional programs that promote the expression of molecules at the origin of an immune permissive TME.

    STEMNESS AND TUMOR IMMUNE MICROENVIRONMENT

    Cancer stem cells (CSCs) are a key component of TME that play important roles in cancer initiation and progression, and therapy resistance.A strong link between CSC and the immune ecosystem has recently been highlighted[32,33].Several immunohistochemistry studies on human samples have demonstrated a good correlation between stemness and immunity markers in tumors.Based on a signature of five stemnessrelated genes, a stemness-related prognostic index (SPI) was calculated in the head and neck squamous cell carcinomas (HNSCC).It was shown that the high-SPI group with poor prognosis had a “cold”immunologic profile, characterized by an increased number of TAMs and CAFs, and a low level of CD8+T and B cells.On the opposite, the SPI-low group of HNSCC displays an increased number of CD8+T cells,aligning the characteristic of inflamed/mesenchymal subtype[34].Based on comprehensive bioinformatic analyses, it has been shown that CRC patients with higher stemness scores exhibited a worse prognosis, a higher immunosuppressive TME, and lower immunotherapeutic responses[35].Several explanations may justify the link between cancer stem cells and immunosuppressive TME.It is known that CSCs express a higher level of PD-L1 than cancer cells, with the existence of a positive association between CSC expansion and a high PD-L1 expression in TME.CSCs also express B7.1 (CD80), another antitumor checkpoint, and CD47.Together, PD-L1, CD80, and CD47 prevent an antitumor immune response.CSCs are also characterized by a low expression of major histocompatibility complex-1 (MHC-1) molecules or antigen processing and presentation machinery, which contributes to lower immunogenicity in these cells, enabling CSCs to escape the immune system[36,37].In summary, CSCs regulate the TME by inhibiting the antitumor immunity; they suppress CD8+T cell infiltration and promote the recruitment of type 2 macrophages (M2).Furthermore, by recruiting macrophages, CSCs build a niche for maintaining their stemness features[38].

    EMT, STEMNESS, AND IMMUNE MICROENVIRONMENT IN CHOLANGIOCARCINOMA

    CCA contains a high contingency of CSCs, i.e., 30%, and many cancer cells express epithelial and mesenchymal markers[39-42].Although a link between EMT and stemness is well established in this tumor with major consequences on tumor progression and drug resistance[43-45], there are few studies related to cancer cell plasticity and immune evasion in CCA.The first study is related to atypical protein kinase C-iota(aPKC-?)[46].Overexpression of aPKC-? in malignant CCA cells promotes EMT by upregulating SNAI1 expressionviathe phosphorylation of the transcription factor Sp1, providing cells with mesenchymal-like features.Within a mesenchymal phenotype, tumor cells indirectly induce Treg‐like cells through other immune cells or by secreting immunosuppressive cytokines, partly mediated by Treg‐inducible cytokines such as IL‐2 and TGF‐β1[46].More recently, it has been demonstrated that CCA malignant cells with high stemness traits express a lower level of MHC-2 molecules than tumor cells with low stemness features[37].In addition, high stemness malignant cells express high levels of inflammatory factors, contributing to immune evasion[47].

    Mutual crosstalk between CSCs and TAMs has been emphasized in CCA[48-51].The two cell types are important CCA cell contingents comprising 30% CSCs and 10% TAMs[39,52].Recently, it has been demonstrated that CSCs derived from CCA cell lines (HuCC-T1 or SB1) express CD11b, a surface marker for macrophages, leading to increased infiltration of macrophages in CSCs-derived tumors in immunodeficient mice[49].CSCs from CCA also produce soluble molecules involved in the differentiation,activation, and recruitment of macrophages[48], enabling the formation of a tumorigenic niche essential for maintaining CSC characteristics[38,49].Among these molecules, IL13, IL34 and osteoactivin have been identified in the CSC secretome at the origin of macrophagic-based niche[48].Furthermore, macrophages produce and secrete TGF-β1 promoting EMT in CCA cellsviaa Smad2/3-GLI2 signaling pathway[50,53].As previously mentioned, TGF-β1 is a prototypic inducer of EMT, which displays immunosuppressive properties[54].In addition to macrophages, CAFS produce pleiotropic factors attracting immune suppressive cells such as MDSCs.By recruiting MDSCs through a 5-LO/LTB4-BLT2 axis, CAFs contribute to increasing the stemness of malignant cells[55,56].

    With the advent of single-cell RNA sequencing, dissecting the TME of CCA has shed light on information regarding TME cell populations and malignant cell heterogeneity.A molecular classification of intrahepatic-CCA (iCCA) based on stroma, tumor, and immune microenvironment elements has evidenced a hepatic stem-like class enriched in M2-like macrophage[51].In peripheral small duct type iCCA (iCCApps), tumor cells positive for the inhibitor of DNA binding and differentiation 3 (ID3) were identified; ID3 is known to contribute to the acquisition of a molecular stem cell-like signature[57].Along with ID3, tumor cells express several stemness markers, such as ZEB1 or LGR5.Even if no correlative studies between ID3+and immune cells were performed in this work, iCCAppscontaining CD3+cells display an infiltration of CD3+T cells and CD56+NK cells, less M2-like phenotype macrophages and a better prognosis[57], suggesting that in this specific subtype of iCCA, stemness phenotype is linked to a better antitumor immunity.Of note, further studies are needed to confirm this speculative conclusion.

    In another cancer of the biliary epithelium, gallbladder cancer, the inhibitory immune checkpoints CD73 and PD-L1 are closely associated with both EMT and stemness phenotypes.Knockdown of CD73 or PD-L1 reduced the proliferative and migratory functions of cancer cells, suggesting that CD73 and PD-L1 are two potential targets to consider as therapeutic strategies for treating tumors containing high populations of cells with CSC and EMT features[58].

    CONCLUSION

    Cell plasticity refers to the ability of cells to change their identity and behavior in response to different cues or stimuli.This phenomenon is particularly relevant in cancer, as it plays a crucial role in tumor progression, metastasis, and therapeutic resistance.Cancer cells can undergo various forms of plasticity,allowing them to adapt to different microenvironments and evade the body's immune system.In CCA, the immune landscape is the subject of numerous studies and reviews that describe the immune cells in partnership with other TME cells at the origin of the immunosuppressive environment[59-61].EMT is a key process associated with malignant cell plasticity in tumors.EMT enables malignant epithelial cells to acquire mesenchymal properties, such as enhanced mobility and invasiveness.These transitions facilitate the invasion of cancer cells into surrounding tissues, dissemination to distant sites, and the formation of secondary tumors through a reverse process called mesenchymal to epithelial transition (MET).Besides tumor dissemination, EMT represents a non-genetic adaptive pathway for cells to survive upon therapeutic pressure and to escape the immune system, both adaptive and innate.

    EMT can confer stemness properties to cancer cells, which may also contribute to the loss of immunosurveillance.Thus, cell plasticity including EMT or stemness has become a crucial biological way for malignant cells to evade the anti-cancer immune system.The molecular mechanisms behind this process have started to be elucidated, but this domain of research remains in its early stages in CCA.However, the strong relationship established between cell plasticity and immune TME may have an impact on clinical implications for prognosis evaluation.Indeed, the presence of cancer cells with mesenchymal or CSC markers could be a sign of an immunosuppressive TME by the work of Jobet al., in which they classify iCCA according to a stromal signature[62].The authors established a classification of four immune subtypes.Interestingly, the fourth subtype, which is not an immunogenic subtype, displays a signature of CSC, EMT,and TGF-β1 signaling[62].This classification is therefore important for selecting proper treatments and considering combinatorial therapies.Currently, an immune checkpoint inhibitor, durvalumab, combined with chemotherapy, is administered to CCA patients.Other combination treatments could be considered,such as metronidazole, which reduces the number of stem cells in preclinical models of CCA[63].Further information on various therapeutic approaches to eradicate cancer stem cells in liver is well discussed in this review[41].Strategies targeting EMT regulators could form part of the therapeutic arsenal to reduce the mesenchymal characteristics of cancer cells undergoing EMT and enhance the efficacy of immune checkpoint inhibitors.For instance, anti-vimentin therapies seem promising[64]; in the case of CCA, this could be relevant since vimentin is highly expressed[39,65].In conclusion, little is known about cellular plasticity in CCA and its link with the immune microenvironment.A better understanding of this link could lead to improved CCA patient management, in particular by proposing more effective combination therapies.

    DECLARATIONS

    Authors’ contributions

    Wrote the first version of the article: Fouassier L

    Edited and approved the final version: Minini M, Pavy A, Lekbaby B

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship

    Minini M and Fouassier L received financial support from ITMO Cancer of Aviesan within the 2021-2030 Cancer Control Strategy framework on funds administered by Inserm.

    Conflicts of interest

    All authors declared that there are no conflicts of interest.

    Ethical approval and consent to participate

    Not applicable.

    Consent for publication

    Not applicable.

    Copyright

    ? The Author(s) 2024.

    国产精品久久久久久精品古装| 高清av免费在线| 五月伊人婷婷丁香| 99久久中文字幕三级久久日本| 亚洲国产欧美人成| 亚洲最大成人手机在线| 亚洲国产成人一精品久久久| 99久久人妻综合| 久久精品熟女亚洲av麻豆精品| 精品少妇黑人巨大在线播放| 男女啪啪激烈高潮av片| 精品一区二区免费观看| 日本爱情动作片www.在线观看| 中文乱码字字幕精品一区二区三区| 极品教师在线视频| 国产久久久一区二区三区| 欧美潮喷喷水| 三级男女做爰猛烈吃奶摸视频| 亚洲精品自拍成人| 免费不卡的大黄色大毛片视频在线观看| 国产一区二区亚洲精品在线观看| 精品久久久精品久久久| 18禁动态无遮挡网站| av黄色大香蕉| 精品酒店卫生间| 在线看a的网站| 亚洲成人中文字幕在线播放| 久久久精品欧美日韩精品| 久久午夜福利片| 久久久久性生活片| 国产成人a区在线观看| 男女啪啪激烈高潮av片| av免费观看日本| 久久久久久伊人网av| 色哟哟·www| 国产在视频线精品| 亚洲美女搞黄在线观看| 欧美老熟妇乱子伦牲交| 男的添女的下面高潮视频| 黄片wwwwww| 欧美少妇被猛烈插入视频| 亚洲高清免费不卡视频| 欧美丝袜亚洲另类| 国产大屁股一区二区在线视频| 波多野结衣巨乳人妻| 国产高清不卡午夜福利| 少妇被粗大猛烈的视频| 免费观看性生交大片5| 国产人妻一区二区三区在| 欧美高清性xxxxhd video| 尾随美女入室| 国产极品天堂在线| 中文精品一卡2卡3卡4更新| 啦啦啦中文免费视频观看日本| 麻豆成人午夜福利视频| 尤物成人国产欧美一区二区三区| 欧美激情久久久久久爽电影| 亚洲天堂av无毛| 日韩av免费高清视频| 六月丁香七月| 国产人妻一区二区三区在| 少妇熟女欧美另类| 中国国产av一级| 少妇被粗大猛烈的视频| 精品久久久久久电影网| 一边亲一边摸免费视频| 噜噜噜噜噜久久久久久91| 欧美激情在线99| 中国国产av一级| 欧美性猛交╳xxx乱大交人| 国产亚洲5aaaaa淫片| 五月开心婷婷网| 91久久精品电影网| 黄片wwwwww| 国国产精品蜜臀av免费| 国产成人a∨麻豆精品| 久久精品夜色国产| 又爽又黄a免费视频| 日日摸夜夜添夜夜添av毛片| 九九在线视频观看精品| 亚洲av国产av综合av卡| 亚洲av.av天堂| 久久人人爽av亚洲精品天堂 | 麻豆久久精品国产亚洲av| 欧美日韩精品成人综合77777| 高清av免费在线| 精品久久久久久久末码| 日本一二三区视频观看| 啦啦啦啦在线视频资源| 久久久a久久爽久久v久久| 在线播放无遮挡| 在线a可以看的网站| 神马国产精品三级电影在线观看| 精品久久久久久电影网| 美女xxoo啪啪120秒动态图| 国产在视频线精品| 蜜桃亚洲精品一区二区三区| 欧美潮喷喷水| 99精国产麻豆久久婷婷| 欧美亚洲 丝袜 人妻 在线| 国产欧美另类精品又又久久亚洲欧美| 啦啦啦中文免费视频观看日本| 午夜激情福利司机影院| 精品一区二区三卡| 国产免费一级a男人的天堂| 国产男人的电影天堂91| 午夜老司机福利剧场| 香蕉精品网在线| 欧美一级a爱片免费观看看| 亚洲精品一二三| 永久免费av网站大全| 亚洲国产精品专区欧美| 欧美一区二区亚洲| 最近2019中文字幕mv第一页| 中文字幕久久专区| 亚洲经典国产精华液单| 大话2 男鬼变身卡| 视频区图区小说| 欧美性感艳星| 国产片特级美女逼逼视频| 久久精品国产鲁丝片午夜精品| 国产成人午夜福利电影在线观看| 寂寞人妻少妇视频99o| 国产精品av视频在线免费观看| 99九九线精品视频在线观看视频| 国产精品嫩草影院av在线观看| 特大巨黑吊av在线直播| 日韩欧美一区视频在线观看 | 久久97久久精品| 少妇人妻精品综合一区二区| 精品亚洲乱码少妇综合久久| 高清视频免费观看一区二区| 久久精品国产亚洲网站| 国产高清国产精品国产三级 | 午夜老司机福利剧场| 国产在线一区二区三区精| 一个人看视频在线观看www免费| 男人舔奶头视频| 国产亚洲最大av| 亚洲精品第二区| 少妇猛男粗大的猛烈进出视频 | 人妻夜夜爽99麻豆av| 免费电影在线观看免费观看| 嫩草影院入口| 性色av一级| 国产色婷婷99| 伦理电影大哥的女人| 22中文网久久字幕| 亚洲欧洲日产国产| 亚洲国产色片| 国产一区有黄有色的免费视频| 免费少妇av软件| 日韩国内少妇激情av| 人体艺术视频欧美日本| 精品人妻视频免费看| 日韩大片免费观看网站| 久久ye,这里只有精品| 国产 精品1| 亚洲三级黄色毛片| 我的老师免费观看完整版| 最新中文字幕久久久久| 日韩成人av中文字幕在线观看| 免费在线观看成人毛片| 国产色婷婷99| 成年版毛片免费区| 中文字幕av成人在线电影| 一区二区av电影网| 最近中文字幕高清免费大全6| 久久人人爽人人片av| 亚洲三级黄色毛片| 亚洲精品aⅴ在线观看| 一本—道久久a久久精品蜜桃钙片 精品乱码久久久久久99久播 | 精品一区二区三区视频在线| 亚洲av成人精品一区久久| 亚洲av二区三区四区| 久久国产乱子免费精品| 日韩强制内射视频| 国产美女午夜福利| 成人欧美大片| 国产女主播在线喷水免费视频网站| 亚洲精品乱久久久久久| 欧美成人一区二区免费高清观看| 下体分泌物呈黄色| 青春草亚洲视频在线观看| 91精品伊人久久大香线蕉| 亚洲精品456在线播放app| 亚洲在久久综合| 国产精品无大码| 男女国产视频网站| 99久久精品国产国产毛片| 亚洲精品一区蜜桃| 人妻制服诱惑在线中文字幕| 身体一侧抽搐| 国产精品久久久久久精品电影| 最近中文字幕高清免费大全6| 青春草国产在线视频| 国产在线男女| 成人毛片a级毛片在线播放| 少妇人妻久久综合中文| av国产久精品久网站免费入址| 国产精品蜜桃在线观看| 国产探花极品一区二区| 亚洲欧美精品专区久久| 一级二级三级毛片免费看| 久久久久国产精品人妻一区二区| 午夜精品一区二区三区免费看| 国产女主播在线喷水免费视频网站| 亚洲欧美成人综合另类久久久| 日本av手机在线免费观看| 欧美丝袜亚洲另类| 亚洲人成网站在线观看播放| 欧美三级亚洲精品| 精品久久久久久电影网| av国产久精品久网站免费入址| 熟妇人妻不卡中文字幕| 亚洲在久久综合| 国产一区二区在线观看日韩| 午夜福利视频精品| 日日啪夜夜爽| 夜夜看夜夜爽夜夜摸| 亚洲国产欧美在线一区| 国产免费一区二区三区四区乱码| 日日啪夜夜爽| 夜夜看夜夜爽夜夜摸| xxx大片免费视频| 久久久久精品性色| 成人欧美大片| 亚洲av欧美aⅴ国产| 一级a做视频免费观看| 热99国产精品久久久久久7| 欧美97在线视频| 亚洲精品aⅴ在线观看| 国产一区二区亚洲精品在线观看| 午夜激情福利司机影院| 伦精品一区二区三区| 国产一区二区在线观看日韩| 亚洲色图综合在线观看| 成人二区视频| 赤兔流量卡办理| 亚洲av国产av综合av卡| 国产精品精品国产色婷婷| 亚洲精品中文字幕在线视频 | 日本色播在线视频| 综合色丁香网| 18禁动态无遮挡网站| .国产精品久久| 免费av毛片视频| 亚洲最大成人手机在线| 男女无遮挡免费网站观看| 亚洲精品视频女| 我要看日韩黄色一级片| 啦啦啦啦在线视频资源| 免费av观看视频| 国产精品福利在线免费观看| 69av精品久久久久久| 国产久久久一区二区三区| 老司机影院毛片| 色吧在线观看| 久久6这里有精品| 国产爽快片一区二区三区| 久久女婷五月综合色啪小说 | 春色校园在线视频观看| 夜夜爽夜夜爽视频| 乱系列少妇在线播放| 午夜免费男女啪啪视频观看| 久久久午夜欧美精品| 久久综合国产亚洲精品| 成人亚洲精品av一区二区| 老司机影院毛片| 亚洲自偷自拍三级| 亚洲成人久久爱视频| 国产在线男女| 深夜a级毛片| 欧美zozozo另类| 亚洲国产精品国产精品| av.在线天堂| 亚洲精品国产成人久久av| 婷婷色av中文字幕| 成年版毛片免费区| 免费不卡的大黄色大毛片视频在线观看| 好男人在线观看高清免费视频| 亚洲人成网站在线观看播放| 2022亚洲国产成人精品| 黄色怎么调成土黄色| 狠狠精品人妻久久久久久综合| 成人亚洲精品一区在线观看 | 亚洲精品视频女| 亚洲精品久久午夜乱码| 久久精品国产鲁丝片午夜精品| 亚洲欧美精品自产自拍| a级毛片免费高清观看在线播放| 成年免费大片在线观看| 国产成人精品福利久久| 美女国产视频在线观看| 国产片特级美女逼逼视频| 高清视频免费观看一区二区| 亚洲av.av天堂| 国产人妻一区二区三区在| 亚洲无线观看免费| 最新中文字幕久久久久| 国产亚洲av嫩草精品影院| 国产在线男女| 精华霜和精华液先用哪个| 能在线免费看毛片的网站| 免费人成在线观看视频色| 久久99蜜桃精品久久| 在线观看免费高清a一片| 亚洲av成人精品一区久久| 亚洲精品日韩在线中文字幕| 一区二区三区四区激情视频| 伊人久久国产一区二区| 国产精品久久久久久久电影| 久久人人爽人人爽人人片va| 建设人人有责人人尽责人人享有的 | 亚洲精品乱码久久久久久按摩| 亚洲av一区综合| 亚洲不卡免费看| 人妻夜夜爽99麻豆av| 18禁在线播放成人免费| 成年av动漫网址| 国产老妇女一区| 久久久精品94久久精品| 香蕉精品网在线| 久久女婷五月综合色啪小说 | 在线免费观看不下载黄p国产| 久久鲁丝午夜福利片| 国产成人免费观看mmmm| 亚洲成人久久爱视频| 久久鲁丝午夜福利片| 免费av毛片视频| 狂野欧美白嫩少妇大欣赏| 亚洲国产日韩一区二区| 爱豆传媒免费全集在线观看| 国产乱来视频区| 国产高清不卡午夜福利| 国国产精品蜜臀av免费| 欧美极品一区二区三区四区| 亚洲欧美精品自产自拍| 深爱激情五月婷婷| 精品亚洲乱码少妇综合久久| 中文字幕av成人在线电影| 国产av国产精品国产| 夜夜爽夜夜爽视频| 深夜a级毛片| 99久久精品国产国产毛片| 中文资源天堂在线| 国产成人免费观看mmmm| 99热全是精品| 国产老妇女一区| 精品少妇久久久久久888优播| 成年女人在线观看亚洲视频 | 中文字幕制服av| av在线蜜桃| 欧美激情在线99| 亚洲欧美成人精品一区二区| 久久99热这里只有精品18| 日本欧美国产在线视频| 亚洲,欧美,日韩| 国产亚洲91精品色在线| 亚洲人成网站在线播| 国产成人精品久久久久久| 偷拍熟女少妇极品色| 亚洲图色成人| 婷婷色麻豆天堂久久| av国产久精品久网站免费入址| 另类亚洲欧美激情| 亚洲欧美成人综合另类久久久| 久久久久精品性色| 五月开心婷婷网| 亚洲国产欧美人成| 亚洲美女搞黄在线观看| 亚洲精品亚洲一区二区| 精品久久久精品久久久| 伦精品一区二区三区| 2018国产大陆天天弄谢| 18禁动态无遮挡网站| 1000部很黄的大片| av国产精品久久久久影院| 黄色欧美视频在线观看| 久久国产乱子免费精品| 中文乱码字字幕精品一区二区三区| 日韩,欧美,国产一区二区三区| 午夜激情久久久久久久| 欧美日韩亚洲高清精品| 在线看a的网站| 丝袜美腿在线中文| 99久久精品一区二区三区| 亚洲欧美成人综合另类久久久| 51国产日韩欧美| 国产精品一区二区在线观看99| 丰满乱子伦码专区| 精品人妻一区二区三区麻豆| 一区二区三区精品91| 亚洲精品国产av成人精品| 在线精品无人区一区二区三 | av在线天堂中文字幕| 日本一本二区三区精品| 婷婷色综合大香蕉| 精品人妻熟女av久视频| 女人久久www免费人成看片| 亚洲av福利一区| 在线亚洲精品国产二区图片欧美 | 男女国产视频网站| 观看免费一级毛片| 3wmmmm亚洲av在线观看| 97精品久久久久久久久久精品| 一级av片app| 2021天堂中文幕一二区在线观| 一本一本综合久久| 国产欧美亚洲国产| 偷拍熟女少妇极品色| 亚洲精品一二三| 国产亚洲最大av| 欧美一级a爱片免费观看看| 男女下面进入的视频免费午夜| 99热6这里只有精品| 国产高清不卡午夜福利| 视频中文字幕在线观看| 亚洲三级黄色毛片| 久久久久久伊人网av| 欧美成人午夜免费资源| 神马国产精品三级电影在线观看| 免费观看的影片在线观看| 黄色配什么色好看| 我要看日韩黄色一级片| 中文字幕久久专区| 久久久久久久久大av| 国产v大片淫在线免费观看| 久久久午夜欧美精品| 男人爽女人下面视频在线观看| 波野结衣二区三区在线| 一级毛片久久久久久久久女| 在线播放无遮挡| 久久99热这里只频精品6学生| 成人免费观看视频高清| 99久国产av精品国产电影| 中文字幕av成人在线电影| 性色av一级| 少妇丰满av| 涩涩av久久男人的天堂| 亚洲国产欧美人成| 特级一级黄色大片| 97热精品久久久久久| 寂寞人妻少妇视频99o| 久久精品夜色国产| 3wmmmm亚洲av在线观看| 久久久a久久爽久久v久久| 精品久久久久久久久av| 尾随美女入室| 六月丁香七月| 交换朋友夫妻互换小说| 男人狂女人下面高潮的视频| 亚洲av.av天堂| 成人一区二区视频在线观看| 亚洲av一区综合| 人人妻人人澡人人爽人人夜夜| 美女cb高潮喷水在线观看| 国内少妇人妻偷人精品xxx网站| 99热6这里只有精品| 五月伊人婷婷丁香| 男女那种视频在线观看| 亚洲最大成人av| 特级一级黄色大片| 18禁裸乳无遮挡免费网站照片| 1000部很黄的大片| 成人二区视频| 99久久中文字幕三级久久日本| 欧美潮喷喷水| 国产黄片视频在线免费观看| 亚洲成色77777| 老司机影院成人| 蜜臀久久99精品久久宅男| 久久久久久久国产电影| 自拍欧美九色日韩亚洲蝌蚪91 | 亚洲av成人精品一区久久| 久久久久久久午夜电影| 黄色一级大片看看| 在线 av 中文字幕| 国产一区二区三区av在线| 久久精品国产亚洲av天美| 亚洲精品色激情综合| 18+在线观看网站| 69人妻影院| 国产av码专区亚洲av| 亚洲va在线va天堂va国产| 欧美精品人与动牲交sv欧美| 香蕉精品网在线| 丰满人妻一区二区三区视频av| 午夜激情久久久久久久| 亚洲人成网站在线观看播放| 一二三四中文在线观看免费高清| 国产成人精品久久久久久| 日韩一区二区三区影片| 精品一区二区免费观看| 可以在线观看毛片的网站| 在线观看美女被高潮喷水网站| 色网站视频免费| 亚洲欧美中文字幕日韩二区| 美女主播在线视频| 又黄又爽又刺激的免费视频.| 搡老乐熟女国产| 成人免费观看视频高清| 黄色视频在线播放观看不卡| 亚洲精品成人久久久久久| 国产高清三级在线| 一级毛片久久久久久久久女| 全区人妻精品视频| 国产亚洲一区二区精品| 最近最新中文字幕免费大全7| 18+在线观看网站| 嫩草影院入口| 欧美精品人与动牲交sv欧美| 中文字幕免费在线视频6| 黑人高潮一二区| 国产精品国产av在线观看| 国精品久久久久久国模美| 国产精品一区二区性色av| 一级av片app| 国产成年人精品一区二区| 色5月婷婷丁香| 最后的刺客免费高清国语| 亚洲精品日韩在线中文字幕| 国产在线一区二区三区精| 欧美少妇被猛烈插入视频| 成人免费观看视频高清| 亚洲人与动物交配视频| 99久久精品热视频| 欧美变态另类bdsm刘玥| 18禁在线无遮挡免费观看视频| 久久精品人妻少妇| 国产在线一区二区三区精| 男女国产视频网站| 色网站视频免费| 久久精品国产亚洲网站| 我的女老师完整版在线观看| 亚洲无线观看免费| 婷婷色综合www| 自拍偷自拍亚洲精品老妇| 新久久久久国产一级毛片| 青春草亚洲视频在线观看| 美女脱内裤让男人舔精品视频| 麻豆乱淫一区二区| 精品一区二区免费观看| 日韩成人伦理影院| 国产亚洲av嫩草精品影院| 国产真实伦视频高清在线观看| 高清在线视频一区二区三区| 噜噜噜噜噜久久久久久91| 99视频精品全部免费 在线| 天堂俺去俺来也www色官网| 亚洲一级一片aⅴ在线观看| 尾随美女入室| 亚洲四区av| 哪个播放器可以免费观看大片| 亚洲三级黄色毛片| 少妇猛男粗大的猛烈进出视频 | 啦啦啦啦在线视频资源| av又黄又爽大尺度在线免费看| 亚洲在久久综合| 精品一区二区三区视频在线| 在线观看一区二区三区| 久久久精品免费免费高清| 卡戴珊不雅视频在线播放| 午夜福利高清视频| 久久精品国产鲁丝片午夜精品| 在线观看国产h片| 亚洲电影在线观看av| 欧美3d第一页| 国产av不卡久久| 国产白丝娇喘喷水9色精品| 午夜激情福利司机影院| 免费电影在线观看免费观看| 久久精品国产亚洲av涩爱| av女优亚洲男人天堂| 国产精品av视频在线免费观看| 亚洲欧美成人精品一区二区| 99久久精品国产国产毛片| 欧美日韩精品成人综合77777| 美女被艹到高潮喷水动态| 国产精品久久久久久av不卡| 蜜臀久久99精品久久宅男| 亚洲人成网站高清观看| 女人十人毛片免费观看3o分钟| 亚洲精品乱码久久久久久按摩| videos熟女内射| 精品少妇久久久久久888优播| av网站免费在线观看视频| 伊人久久国产一区二区| 一级毛片久久久久久久久女| 纵有疾风起免费观看全集完整版| 国产久久久一区二区三区| 一级二级三级毛片免费看| 麻豆久久精品国产亚洲av| 欧美成人午夜免费资源| 欧美性感艳星| 亚洲精品aⅴ在线观看| 亚洲国产精品国产精品| 视频中文字幕在线观看| 午夜福利高清视频| videos熟女内射| 一区二区三区四区激情视频| 男人舔奶头视频| 亚洲av成人精品一区久久| 卡戴珊不雅视频在线播放| 欧美亚洲 丝袜 人妻 在线| 成人综合一区亚洲| 好男人视频免费观看在线| 精品人妻视频免费看| 99久久精品一区二区三区| 国产av国产精品国产| 成人毛片60女人毛片免费| 久久久久久久久久久丰满| 天美传媒精品一区二区| 男女边摸边吃奶| 在线观看一区二区三区激情|