HPV感染后微環(huán)境在子宮頸癌發(fā)生發(fā)展中的研究進(jìn)展

21.66%[1],面臨著嚴(yán)峻的子宮頸癌疾病負(fù)擔(dān)。HPV屬于非包膜DNA病毒，其見(jiàn)圖1。(一)角質(zhì)形成細(xì)胞角質(zhì)形成細(xì)胞具有Toll樣受體(Tol1-likereceptors,TLR)和維甲酸誘導(dǎo)型基因I受體(retinoicacid-induciblegeneI,RIG-I)等多種病原體識(shí)別受體，作為先天性免疫細(xì)胞發(fā)揮抗病毒作用[3]。然而，HPV干擾角質(zhì)E5、E6和E7蛋白抑制角質(zhì)形成細(xì)胞的先天性免疫反應(yīng)[4]。HPVE5蛋白限制細(xì)遞呈的抗原庫(kù)[5]。HPVE6和E7蛋白則通過(guò)誘導(dǎo)泛素C末端水解酶L1(ubiquitincarboxy-terminalhydrolaseL1,UCHL1)限制腫瘤壞死因子受體相關(guān)的激活，并抑制干擾素調(diào)節(jié)因子(interferonregulatorytranscriptionfactor,IRF)3二聚體的核轉(zhuǎn)位，從而抑制干擾素表達(dá)[6]。HPV18型E7蛋白抑制環(huán)磷酸鳥苷-磷酸腺苷酸合成酶(cyclicGMP-AMPsynthase,cGAS)-干擾素基因刺激物(stimulatorofinterferongenes,STING)信號(hào)軸[7]。HPV16型E7蛋白抑制γ干擾素誘導(dǎo)的信號(hào)傳導(dǎo)及轉(zhuǎn)錄激活蛋白1(signaltransducerandactivatoroftranscription,STAT1)的磷酸化，抑制IRF-1和轉(zhuǎn)運(yùn)體相關(guān)抗原處理亞基1(transporterassociatedwithantigenprocessing,TAP-1)的表達(dá)，降低角質(zhì)形成細(xì)胞表面MHC-I類抗原的遞呈效率[8]?？傊?，這些通路通過(guò)改變角質(zhì)形成細(xì)胞的特征、干擾免疫介質(zhì)，促進(jìn)PIM的形成。IFNAR1-角質(zhì)形成細(xì)胞DI①IODWND①0II4TLR、RIG-3;UCHL1表示泛素C末端水解酶L1;TBK1表示TANK結(jié)合激酶1;IKKe表示IkB激酶e;IRF表示干擾素(二)免疫細(xì)胞1.抗原遞呈細(xì)胞：抗原遞呈細(xì)胞(antigen-presentingcell,APC)是PIll,DC)、朗格漢斯細(xì)胞(Langerhanscell,LC)和B淋巴細(xì)胞等。當(dāng)巨噬細(xì)胞進(jìn)入PIM時(shí)，被富含血管內(nèi)皮生長(zhǎng)因子(vascularendothelialgrowthfactor,VEGF)、白細(xì)胞介素(interleukin,IL)6和IL-8的微環(huán)境極化為M1I類抗原表達(dá)減少，逃避了T淋巴細(xì)胞的識(shí)別[12]。CD4+調(diào)節(jié)性T淋巴細(xì)胞可eta,TGF-β)促進(jìn)子宮頸癌進(jìn)展[13]。在PIM中，調(diào)節(jié)性B淋巴細(xì)胞能夠產(chǎn)生IL-10抑制CD8+T淋巴細(xì) K細(xì)胞的活性受損[15];另一方面，HPV破壞NK細(xì)胞的種群平衡，使NK細(xì)胞因子(fibroblastgrowthfactor,FGF)的敏感性增加[17]。感染HPV16型進(jìn)血管生成和腫瘤細(xì)胞生長(zhǎng)[18]。病毒拷貝數(shù)病毒拷貝數(shù)病毒組裝與釋放早期癌蛋白基底層基底膜腫瘤細(xì)胞樹突狀細(xì)胞巨嗟細(xì)胞T淋巴細(xì)胞B淋巴細(xì)胞1細(xì)胞外基質(zhì)隨系抑制性細(xì)胞NK細(xì)胞乳酸效應(yīng)晚期癌蛋白腫雇相關(guān)環(huán)氧合酶2;sTREM-1表示可溶性髓系細(xì)胞表達(dá)的觸發(fā)受體1;AP-1表示激活蛋白1;IL表示白細(xì)胞介素；ECM表示細(xì)胞外基質(zhì)；YAP表示Yes相關(guān)蛋白；EMT表示上皮-間質(zhì)轉(zhuǎn)化；LDHA表示乳酸脫氫酶A;圖2感染后微環(huán)境(PIM)誘導(dǎo)子宮頸癌發(fā)生發(fā)展的模型。HPV病毒顆粒通過(guò)微磨損穿透上皮到達(dá)角質(zhì)形成細(xì)胞。HPV感染后的角質(zhì)形成細(xì)胞積極塑造PIM,從免疫抑制微環(huán)境、炎癥和氧化應(yīng)激、ECM重塑、1.免疫抑制微環(huán)境促進(jìn)HPV持續(xù)感染：癌基因過(guò)度表達(dá)而產(chǎn)生的新抗原在細(xì)胞死亡后被釋放和捕獲，然后被APC遞呈給T淋巴細(xì)胞，激活效應(yīng)T淋巴細(xì)胞殺死癌細(xì)胞，導(dǎo)致更多抗原的釋放。這個(gè)循環(huán)過(guò)程被定義為癌癥免疫循環(huán)。然而，在高級(jí)別子宮頸病變中腫瘤相關(guān)巨噬細(xì)胞(CD163+CD68+)浸潤(rùn)增加，γ干擾素宮頸癌細(xì)胞免疫逃逸[23]。2(cyclooxygenase-2,COX-2)、可溶性髓系細(xì)胞表達(dá)的觸發(fā)受體1(so蛋白通過(guò)激活蛋白1(activatorprotein1,AP-1),導(dǎo)致COX-錄因子Yes相關(guān)蛋白(Yes-associatedprotein,YAP),介導(dǎo)癌細(xì)胞的上皮-間質(zhì)轉(zhuǎn)化[26]。管生成活性[27]。血管的基底膜被基質(zhì)金屬蛋白酶(matrixmetalloprotein胞上表達(dá)的VEGF-A受體[28],并促進(jìn)更多的血管生成。腫瘤細(xì)胞通過(guò)血糖酵解中發(fā)揮關(guān)鍵作用[29]。E6蛋白使p53失活，直接抑制微小RNA(miR)生[30]。性死亡受體1(programmedcelldeathprotein1,PD-1)和細(xì)胞毒性T淋巴細(xì)胞相關(guān)抗原4(cytotoxicTlym16型E7蛋白靶向的工程化T淋巴細(xì)胞治療后(NCT02858310),6例(6/12)患者的腫瘤縮小，其中4例為抗PD-1難治性腫瘤[32]。將趨化因子配體11(C (2023年版)[35]推薦，貝伐單抗(bevacizumab)聯(lián)合化療作為復(fù)發(fā)、轉(zhuǎn)移F受體2的酪氨酸激酶活性，延緩子宮頸癌進(jìn)展[36]。歐洲婦科腫瘤試驗(yàn)小組 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