汪 英,李錫春

(1.四川省人民醫(yī)院城東病區(qū),四川成都610101;2.中航工業(yè)成飛醫(yī)院,四川成都610092)

腫瘤樹突狀細(xì)胞疫苗研究進展

汪 英1,李錫春2

(1.四川省人民醫(yī)院城東病區(qū),四川成都610101;2.中航工業(yè)成飛醫(yī)院,四川成都610092)

腫瘤免疫療法在過去的十年被臨床腫瘤學(xué)界視為一種越來越有效的治療模式。近年來,對腫瘤疫苗中的樹突狀細(xì)胞疫苗進行了大量的研究。對腫瘤樹突狀細(xì)胞疫苗研究進展進行簡述,目的是為讀者梳理出腫瘤疫苗的發(fā)展脈絡(luò)。

腫瘤;疫苗;樹突狀細(xì)胞

隨著腫瘤生物學(xué)和免疫學(xué)的發(fā)展,腫瘤免疫治療得到了迅速的發(fā)展。腫瘤免疫療法在過去的十年被臨床腫瘤學(xué)界視為一種越來越有效的治療模式。FDA即批準(zhǔn)了兩個以免疫治療為基礎(chǔ)的產(chǎn)品,一個為治療前列腺癌的Provenge(sipuleuce-T)疫苗,另一個為治療黑色素瘤的抗細(xì)胞毒性T淋巴細(xì)胞相關(guān)抗原4(CTLA-4)的抗體ipilimumab疫苗。

腫瘤疫苗是指可以誘導(dǎo)機體產(chǎn)生針對腫瘤的特異性T細(xì)胞反應(yīng)(包括CD8+和CD4+T細(xì)胞),以抑制或消除腫瘤生長、復(fù)發(fā)或轉(zhuǎn)移的各種形式的疫苗。由于方法不同,可出現(xiàn)很多的腫瘤疫苗分類。目前比較公認(rèn)的分類方法是依據(jù)腫瘤疫苗的來源、作用對象及構(gòu)建載體來進行分類。通常腫瘤疫苗類型包括腫瘤細(xì)胞疫苗、基因工程疫苗、樹突狀細(xì)胞疫苗、病毒疫苗、多肽疫苗、核酸疫苗、抗獨特性抗體疫苗等。1996年美國斯坦福大學(xué)醫(yī)學(xué)中心Hsu等[1]在Nature Medicine上報道了全球首項樹突狀細(xì)胞(dendritic cell,DC)腫瘤疫苗臨床研究,4例濾泡性B淋巴細(xì)胞腫瘤患者接受腫瘤抗原刺激的自體外周血來源DC細(xì)胞治療,試驗結(jié)果令人鼓舞。一項Meta分析表明,接受DC疫苗治療的前列腺癌和腎細(xì)胞癌患者的目標(biāo)應(yīng)答率分別為7.7%和12.7%,臨床受益率分別為54%和48%,總緩解率分別為10.6%和8.4%?，F(xiàn)就腫瘤樹突狀細(xì)胞疫苗及其研究進展簡述如下。

1973年,Steinman和Cohn發(fā)現(xiàn)具有樹枝狀突起的獨特形態(tài)細(xì)胞,并將之命名為樹突狀細(xì)胞。DC參與多種疾病如感染、腫瘤、過敏及移植排斥的發(fā)生與發(fā)展。由于發(fā)現(xiàn)DC及其在獲得性免疫應(yīng)答中的作用,Steinman榮獲2011年諾貝爾生理或醫(yī)學(xué)獎并被譽為DC之父[2-3]。隨著腫瘤免疫學(xué)的發(fā)展,DC作為腫瘤治療手段受到了越來越多的關(guān)注并被寄予厚望。負(fù)載腫瘤抗原的DC疫苗被認(rèn)為是最具潛能的一種腫瘤免疫治療手段[4-5]。關(guān)于DC疫苗的研究主要有以下幾方面。

1 腫瘤抗原肽致敏DC疫苗

腫瘤抗原肽致敏DC具有很好的靶向性,試驗證明,在體內(nèi)、外均能誘導(dǎo)MHC-1和MHC-2的特異性T細(xì)胞反應(yīng)。在體外,單獨的抗原肽則會引起特異性的CTL的耐受,而抗原肽致敏DC后能誘導(dǎo)針對腫瘤細(xì)胞的抗原特異性T細(xì)胞反應(yīng)[4]。經(jīng)DC呈遞的人類或者小鼠的腫瘤抗原/肽能引起顯著性的抗腫瘤免疫反應(yīng)。特別是MHC限制性合成腫瘤相關(guān)肽,如黑色素瘤相關(guān)抗原,內(nèi)源性逆轉(zhuǎn)錄病毒基因產(chǎn)品gp70/p15E,癌胚抗原(CEA),葉酸連接蛋白(FBP),前列腺特異性膜抗原(PMSA),survivin,MUC-1, HER2/neu和抗獨特性衍生的蛋白質(zhì)合成肽, bcr-ɑbl b3a2融合蛋白(ATGFKQSSKALQRPVAS)和一種合成的HPV16E7肽。腫瘤抗原肽致敏DC已在動物研究和臨床試驗中取得不同程度的效果[5-8]。與黑色素瘤相關(guān)的抗原gp100、MART-1、NA17及MAGE家族;與前列腺癌相關(guān)的抗原前列腺特異性膜抗原(PSMA)、前列腺酸性磷酸酶(PAP)、前列腺特異抗原(PSA)。美國FDA批準(zhǔn)用于治療前列腺癌的Sipuleucel-T[9]。目前研究[10]比較深入的腫瘤抗原,已經(jīng)在腫瘤的診斷、預(yù)防和治療方面發(fā)揮著十分重要的作用。腫瘤特異抗原-Her-2/ neu-乳腺癌、前列腺癌、黑色素瘤抗原(MAGE)-黑色素瘤、卵巢癌、肝癌等[11-12]。

腫瘤相關(guān)抗原如腫瘤細(xì)胞裂解物致敏DC同樣能誘導(dǎo)CTL反應(yīng),而且還能誘導(dǎo)輔助性T細(xì)胞免疫反應(yīng)。在兩個獨立品系的且腫瘤組織學(xué)不同小鼠,皮下注射腫瘤裂解物致敏DC,不僅減少腫瘤的體積,還有減少腫瘤肺轉(zhuǎn)移的作用[12]。相似的應(yīng)用在小鼠肝癌細(xì)胞BNL1MEA.7R.1(BNL)、腎癌、同系GL261膠質(zhì)瘤、胰腺癌、惡性腦瘤及卵巢癌[13-15]。已大量研究[16-17]的與B淋巴瘤相關(guān)的CD20,與CA125糖蛋白相關(guān)的腫瘤有卵巢癌、子宮內(nèi)膜癌、宮頸癌、胰腺癌、腸癌、乳腺癌及肺癌。盡管腫瘤抗原研究取得了很大進展,但由于其獲得困難或特異性不強,采用全瘤組織細(xì)胞裂解物沖擊DC成為最直接的一種方法[18].最重要的是,腫瘤裂解物致敏-DC疫苗在人類惡性黑色素瘤、甲狀旁腺瘤、晚期乳腺和子宮癌、腎癌(RCC)及實體腫瘤中均有顯著的獲益[19-20]。

2 RNA轉(zhuǎn)染DC疫苗

與傳統(tǒng)疫苗相比,核酸疫苗可激發(fā)機體全面的免疫應(yīng)答,其表達的抗原肽接近天然構(gòu)象,抗原性更強。而且,m RNA從小鼠腫瘤細(xì)胞株或從人類腫瘤冰凍切片中提取,可隨意擴增而不會喪失其相應(yīng)的功能[21-22]。

腫瘤細(xì)胞的m RNA轉(zhuǎn)染DC能夠刺激荷瘤小鼠全能的CTL反應(yīng)從而產(chǎn)生保護性免疫[23]。盡管大多有效的mRNA呈遞在人類血液細(xì)胞使用的電穿孔技術(shù),大多數(shù)研究者均是用的m RNA/脂質(zhì)體復(fù)合物轉(zhuǎn)染的DCs[24]。因為,用腫瘤m RNA轉(zhuǎn)染DCs激活細(xì)胞內(nèi)信號機調(diào)節(jié)有效的抗原肽呈遞到MHC-1和MHC-II分子,故能顯著的誘導(dǎo)腫瘤特異性的效應(yīng)T細(xì)胞的激活[25-26]。雖然這類疫苗在臨床的應(yīng)用有限,但為癌癥患者誘導(dǎo)潛在的治療性多克隆T細(xì)胞反應(yīng)提供了制備疫苗的策略[27-28]。

3 壞死或凋亡負(fù)荷的DC疫苗

DCs不僅能輕易的攝取可溶性腫瘤抗原如蛋白或免疫復(fù)合物,還能吞噬正在死亡的(如凋亡或壞死)腫瘤細(xì)胞,從而誘導(dǎo)保護性抗腫瘤免疫[29-31]。DCs識別和攝取凋亡細(xì)胞通過其特異性受體如Vb5, CD36或者磷脂酰絲氨酸受體[32],而攝取壞死細(xì)胞通過CD91和暴露在其細(xì)胞表面的(hot shock protein, HSP)受體[33-34]。近來一些比較性研究[35]表明,壞死和晚期凋亡細(xì)胞能同樣觸發(fā)DC成熟性改變從而誘導(dǎo)抗腫瘤免疫。DC吞噬壞死的腫瘤細(xì)胞依靠它們所表達的熱休克蛋白(HSP),進行成熟反應(yīng),伴隨化學(xué)炎癥因子和細(xì)胞因子、共刺激免疫分子表達上調(diào),從而在動物模型中誘導(dǎo)強烈的保護性抗腫瘤免疫[36-39]。

4 基因修飾的DC疫苗

將靶基因?qū)隓C制成的腫瘤疫苗是目前腫瘤疫苗研究的一大熱點,靶基因包括腫瘤相關(guān)抗原(TAA)和免疫調(diào)節(jié)蛋白如細(xì)胞因子或共刺激分子。將基因?qū)隓C的方法很多,包括陽離子脂質(zhì)、電穿孔法、基因槍、用陽離子CL22、非病毒載體T7構(gòu)建的質(zhì)粒DNA的復(fù)合物、病毒載體及病毒/聚陽離子復(fù)合物[40-42]。

4.1 腫瘤相關(guān)抗原轉(zhuǎn)染DC疫苗

在動物模型中,腫瘤相關(guān)抗原(TAA)導(dǎo)入DCs疫苗在體內(nèi)、外比腫瘤抗原致敏DC疫苗具有更強的抗腫瘤免疫反應(yīng),該疫苗能產(chǎn)生更強CD8+T淋巴細(xì)胞免疫反應(yīng),從而誘導(dǎo)出更強的抗腫瘤效應(yīng)[43]。體外已經(jīng)證明,TAA導(dǎo)入DCs疫苗通過激活CD8+T淋巴細(xì)胞而提高抗腫瘤免疫反應(yīng)[44]。MAGE-1, gp100,MART-1,h TRP2,p53,MUC-1及其他一些抗原基因已經(jīng)被用于轉(zhuǎn)入小鼠或人DCs從而誘導(dǎo)抗原特異性免疫反應(yīng)[45-48]。

復(fù)制缺陷性重組腺病毒Ad Vs編碼的人gp100或MART-1黑色素瘤抗原已被用于轉(zhuǎn)入小鼠或人DCs。從轉(zhuǎn)移性黑色素瘤患者體內(nèi)獲取的gp100+制成的Ad2/gp100轉(zhuǎn)入DC獲得的疫苗在體外能誘導(dǎo)腫瘤特異性CTL反應(yīng)[49]。相似的,HLA-A2+/ MART-1細(xì)胞株制成的Ad VMART1轉(zhuǎn)入DC疫苗能產(chǎn)生MART-1免疫肽特異性CTL反應(yīng),免疫荷黑色素瘤B16細(xì)胞的小鼠具有保護性免疫作用[50]。同樣,用重組腺病毒構(gòu)建的HER2/neu(Ad VNeu)轉(zhuǎn)入DC制成的疫苗,可抑制乳腺癌細(xì)胞過表達HER2/neu,同時具有保護性抗腫瘤免疫,能夠誘導(dǎo)針對乳腺癌細(xì)胞的CTL反應(yīng),體內(nèi)激活CD8+T和CD4+T淋巴細(xì)胞免疫反應(yīng)。

4.2 免疫調(diào)節(jié)分子(細(xì)胞因子、趨化因子)轉(zhuǎn)染DC疫苗

上述提到的用抗原轉(zhuǎn)入DC制備的疫苗優(yōu)于直接用抗原或裂解物致敏DC,但需要尋找抗原性較強的抗原。用免疫調(diào)節(jié)蛋白構(gòu)建的DC疫苗可擴大DCs腫瘤抗原的能力,可用于任何類型的具有TAA的腫瘤。因為,DCs是天然專職的抗原呈遞細(xì)胞,能精確的呈遞細(xì)胞因子[51],所以,免疫調(diào)節(jié)分子(GMCSF,TNF-α、IL-12,次級淋巴組織趨化因子SLC,淋巴細(xì)胞趨化因子和CD40L等)修飾的DCs具有比相應(yīng)的調(diào)節(jié)分子修飾腫瘤細(xì)胞疫苗更強的免疫調(diào)節(jié)能力。

GM-CS是DCs在體外生長和分化的必需因子。體內(nèi)免疫時,用GM-CSF轉(zhuǎn)染骨髓起源的BM-DCs的抗原呈遞能力相對模擬轉(zhuǎn)染或未處理的DC有很大的提高,同樣,在半抗原、蛋白抗原、或者腫瘤抗原誘導(dǎo)原始免疫反應(yīng)方面也一樣。而這個能力的提高與該疫苗在體內(nèi)的增強遷移能力顯著相關(guān)。IL-12是一種異源二聚體細(xì)胞因子,由多種類型細(xì)胞產(chǎn)生包括DCs、巨噬細(xì)胞、白細(xì)胞和角質(zhì)形成細(xì)胞。DCs表達的IL-12轉(zhuǎn)基因疫苗與未轉(zhuǎn)染的DC相比能增強特異性抗腫瘤CTL反應(yīng)。用該疫苗免疫荷瘤小鼠(MCA205、B16和D122),在第7天可見腫瘤開始消退,而接種的結(jié)腸腺癌則完全消退。

5 DC疫苗治療腫瘤的臨床研究進展

DCs在腫瘤免疫中的作用NK細(xì)胞的活化同樣受到DCs的調(diào)控,并反饋性調(diào)節(jié)DCs的功能[52]。除了產(chǎn)生有力的抗腫瘤免疫應(yīng)答外,DCs也在腫瘤消除中發(fā)揮作用。Munich,S.等研究[36]報道DCs通過TNF超家族的配基殺死腫瘤,并可以直接抑制腫瘤細(xì)胞系的生長。在成熟過程中,DCs失去了它們有效攝取和加工抗原的能力,取而代之的是遷移能力的增加,使得它們能夠有效的遷移至引流淋巴結(jié)[53];另外,與iDCs相比,mDCs具有不同的細(xì)胞因子和生長因子表達譜[54-56]。

5.1 黑色素瘤

黑色素瘤是由異常黑素細(xì)胞過度增生引發(fā)的常見皮膚腫瘤,惡性程度極高,具有高發(fā)病率和高死亡率特點,研究[57]表明,免疫治療是黑素瘤的有效治療方法。一項對Ⅲ期惡性黑素瘤患者淋巴結(jié)清掃術(shù)后進行的DC疫苗臨床研究[58]證實,22例患者中,治療組的三年總生存率(OS)為68.0%,對照組僅為25.7%。對54個DC疫苗治療黑素瘤的臨床試驗進行回顧性分析,發(fā)現(xiàn)DC是否成熟、腫瘤Ⅲ期和Ⅳ期、是否使用佐劑、是否發(fā)生遲發(fā)性過敏反應(yīng)及分泌IFN-γ的T細(xì)胞數(shù)量增加與否對疾病進展、臨床反應(yīng)及疾病穩(wěn)定具有決定性影響。

5.2 前列腺癌

一項對于Sipuleucel-T成功上市至關(guān)重要的Ⅲ期臨床試驗共入組了512例前列腺癌患者(Sipuleucel-T組341例,安慰劑組171例),結(jié)果表明,與安慰劑組相比,Sipuleucel-T組的死亡風(fēng)險下降了22%,中位生存期延長了4.1 mon(Sipuleucel-T組和安慰劑組分別為25.8和21.7 mon),3 a生存率提高了8.7%。兩組的客觀疾病進展時間無差異。Sipuleucel-T組多見的不良反應(yīng)有寒顫、發(fā)燒和頭痛。一項Sipuleucel-T治療前列腺癌患者的Meta分析表明,納入分析的737例患者總生存期顯著增加。但是,疾病進展時間并沒有增加。受試者的恰當(dāng)選擇從Sipuleucel-T臨床試驗的成功中得到充分體現(xiàn)。Dendreon公司選擇滿足如下入組標(biāo)準(zhǔn)的前列腺癌患者進行臨床研究:①無癥狀或輕微癥狀的轉(zhuǎn)移性去勢抵抗性前列腺癌患者;②預(yù)計生存期不小于6個月;③血清PSA水平不小于5 ng/m L;④血清睪酮水平不大于500 ng/L(17 nmol/L)(排除標(biāo)準(zhǔn): (1)體能狀況評分不小于2(ECOG);(2)有內(nèi)臟轉(zhuǎn)移瘤;(3)病理長骨骨折;(4)脊髓壓迫)。⑤治療前28 d使用了糖皮質(zhì)激素、外放射治療、手術(shù)或全身治療(藥物或手術(shù)去勢除外);⑥在治療前28 d內(nèi)已經(jīng)開始或停止雙膦酸鹽治療;⑦之前已經(jīng)接受超過2個化療方案;⑧治療前3 mon內(nèi)已接受化療。

參考文獻:

[1]Draube A,Klein-Gonzalez N,Mattheus S,et al.Dendritic cell based tumor vaccination in prostate and renal cell cancer:a systematic review and meta-analysis[J].PLoS One,2011,6(4):e18801.

[2]Steinman RM,Cohn ZA.Identification of a novel cell type in peripheral lymphoid organs of micel.Morphology, quantitation,tissue distribution[J].J Exp Med,1973, 137(5):1142―1162.

[3]Palucka K,Banchereau J.Cancer immunotherapy via dendritic cells[J].Nat Rev Cancer,2012,12(4):265―277.

[4]Galluzzi L,Senovilla L,Vacchelli E,et al.Trial watch: Dendritic cell-based interventions for cancer therapy[J]. Oncoimmunology,2012,1(7):1111―1134.

[5]Sabado RL,Bhardwaj N.Dendritic cell immunotherapy [J].Ann N Y Acad Sci,2013,1284(1):31―45.

[6]Lau R,Wang F,Jeffery G,et al.Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma[J].J Immunother,2001,24(1):66―78.

[7]Kershaw M H,Hsu C,Mondesire W,et al.Immunization against endogenous retroviral tumor-associated antigens[J].Cancer Res,2001,61(21):7920―7924.

[8]Fong L,Hou Y,Rivas A,et al.Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy[J].Proc Natl Acad Sci,2001,98 (15):8809―8814.

[9]DeFrancesco L.Landmark approval for Dendreon's cancer vaccine[J].Nat Biotechnol,2010,28(6):531―532.

[10]Baxevanis CN,Voutsas IF,Gritzapis AD,et al.HER-2/neu as a target for cancer vaccines[J].Immunotherapy, 2010,2(2):213―226.

[11]Meek DW,Marcar L.MAGE-A antigens as targets in tumour therapy[J].Cancer Lett,2012,324(2):126―132.

[12]Slovin SF,Kehoe M,Durso R,et al.A phase I dose escalation trial of vaccine replicon particles(VRP)expres sing prostate-specific membrane antigen(PSMA)in subjects with prostate cancer[J].Vaccine,2013,31(6):943―949.

[13]Tatsumi T,Takehara T,Kanto T,et al.Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma[J].Cancer Res,2001,61(20):7563―7567.

[14]Ni H T,Spellman S R,Jean W C,et al.Immunization with dendritic cells pulsed with tumor extract increases survival of mice bearing intracranial gliomas[J].J Neurooncol,2001,51(1):1―9.

[15]Schnurr M,Galambos P,Scholz C,et al.Tumor cell lysate-pulsed human dendritic cells induce a T-cell response against pancreatic carcinoma cells:an in vitro model for the assessment of tumor vaccines[J].Cancer Res,2001, 61:6445―6450.

[16]Manzur S,Cohen S,Haimovich J,et al.Enhanced the rapeutic effect of B cell-depleting anti-CD20 antibodies upon combination with in-situ dendritic cell vaccination in advanced lymphoma[J].Clin Exp Immunol,2012,170 (3):291―299.

[17]Goldman PA.CA 125:Value or addiction?[J].Cancer, 2010,116(12):2854―2855.

[18]DeFrancesco L.Landmark approval for Dendreon's cancer vaccine[J].Nat Biotechnol,2010,28(6):531―532.

[19]Kurokawa T,Oelke M,Mackensen A.Induction and clonal expansion of tumor-specific cytotoxic T lymphocytes from renal cell carcinoma patients after stimulation with autologous dendritic cells loaded with tumor cells [J].Int J Cancer,2001,91(6):749―756.

[20]Santin A D,Bellone S,Ravaggi A,et al.Induction of tumourspecific CD8+cytotoxic T lymphocytes by tumour lysatepulsed autologous dendritic cells in patients with uterine serous papillary cancer[J].Br J Cancer,2002,86 (1):151―157.

[21]Boczkowski D,Nair S K,Nam J H,et al.Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells[J].Cancer Res,2000,60(4): 1028―1034.

[22]Nair S K,Morse M,Boczkowski D,et al.Induction of tumorspecific cytotoxic T lymphocytes in cancer patients by autologous tumor RNA-transfected dendritic cells[J]. Ann Surg,2002,235(4):540.

[23]Van Tendeloo V F,Ponsaerts P,Lardon F,et al.Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells:superiority to lipofection and passive pulsing of m RNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells[J]. Blood,2001,98(1):49―56.

[24]Eppler E,Horig H,Kaufman H L,et al.Carcinoembryonic antigen(CEA)presentation and specific T cellpriming by human dendritic cells transfected with CEAm-RNA[J].Eur J Cancer,2002,38(1):184―193.

[25]Honda K,Sakaguchi S,Nakajima C,et al.Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection[J].Proc Natl Acad Sci,2003,100(19): 10872―10877.

[26]Weissman D,Ni H,Scales D,et al.HIV gag m RNA transfection of dendritic cells(DC)delivers encoded antigen to MHC class I and II molecules,causes DC matura-tion,and induces a potent human in vitro primary immune response[J].J Immunol,2000,165(8):4710―4717.

[27]Rains N,Cannan R J,Chen W,et al.Development of a dendritic cell(DC)-based vaccine for patients with Ad V-sanced colorectal cancer[J].Hepatogastroenterology, 2001,48(38):347―351.

[28]Schmitt W E,Stassar M J,Schmitt W,et al.In vitro induction of a bladder cancer-specific T-cell response by m RNA-transfected dendritic cells[J].J Cancer Res Clin Oncol,2001,127(2):203―206.

[29]Larsson M,Fonteneau J F,Bhardwaj N.Dendritic cells resurrect antigens from dead cells[J].Trends Immunol, 2001,22(3):141―148.

[30]Fonteneau J F,Larsson M,Bhardwaj N.Dendritic celldead cell interactions:implications and relevance for immunotherapy[J].J Immunother,2001,24(4):294―304.

[31]Rovere P,Sabbadini M G,Vallinoto C,et al.Delayed clearance of apoptotic lymphoma cells allows cross-presentation of intracellular antigens by mature dendritic cells [J].J Leukoc Biol,1999,66(2):345―349.

[32]Fadok V A,Bratton D L,Rose D M,et al.A receptor for phosphatidylserine-specific clearance of apoptotic cells [J].Nature,2000,405(6827):85―90.

[33]Basu S,Binder R J,Suto R,et al.Necrotic but not apoptotic cell death releases heat shock proteins,which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway[J].Int Immunol,2000, 12(11):1539―1546.

[34]Binder R J,Han D K,Srivastava P K.CD91:a receptor for heat shock protein gp96[J].Nat Immunol,2000,1 (2):151―155.

[35]Kotera Y,Shimizu K,Mule JJ.Comparative analysis of necrotic and apoptotic tumor cells as a source of antigen (s)in dendritic cell-based immunization[J].Cancer Res, 2001,61(22):8105―8109.

[36]Munich S,Sobo-Vujanovic A,Buchser WJ,et al. Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands[J]. Oncoimmunology,2012,1(7):1074―1083.

[37]Feng H,Zeng Y,Whitesell L,et al.Stressed apoptotic tumor cells express heat shock proteins and elicit tumorspecific immunity[J].Blood,2001,97(11):3505―3512.

[38]Zheng H,Dai J,Stoilova D,et ak.Cell surface targeting of heat shock protein gp96 induces dendritic cell maturation and antitumor immunity[J].J Immunol,2001,167 (12):6731―6735.

[39]Chen Z,Moyana T,Saxena A,et al.Efficient antitumor immunity derived from maturation of dendritic cells that had phagocytosed apoptotic/necrotic tumor cells[J].Int J Cancer,2001,93(4):539―548.

[40]Rughetti A,Biffoni M,Sabbatucci M,et al.Transfected human dendritic cells to induce antitumor immunity[J]. Gene Ther,2000,7(17):1458―1466.

[41]Irvine AS,Trinder P K,Laughton D L,et al.Efficient nonviral transfection of dendritic cells and their use for in vivo immunization[J].Nat Biotechnol,2000,18(12): 1273―1278.

[42]Wei Y,Li J,Chen W Y,et al.Enhanced transgene expression and effective in vivo antitumor immune responses initiated by dendritic progenitors transfected with a nonviral T7 vector expressing a model tumor antigen[J].J Immunother,2000,23(1):75―82.

[43]Ponnazhagan S,Mahendra G,Curiel D T,et al.Ade noassociated virus type 2-mediated transduction of human monocytederived dendritic cells:implications for ex vivo immunotherapy[J].J Virol,2001,75(19):9493―9501.

[44]Xia D,Zheng S,Zhang W,et al.Effective induction of therapeutic antitumor immunity by dendritic cells coexpressing interleukin-18 and tumor antigen[J].J Mol Med,2003,81(9):585―596.

[45]Ribas A,Butterfield L H,Hu B,et al.Generation of T-cell immunity to a murine melanoma using MART-1-engineered dendritic cells[J].J Immunother,2000,23(1): 59―66.

[46]Steitz J,Bruck J,Knop J,et al.Adenovirus-transduced dendritic cells stimulate cellular immunity to melanoma via a CD4(+)T cell-dependent mechanism[J].Gene T-her,2001,8(16):1255―1263.

[47]Nikitina E Y,Clark J I,Van Beynen J,et al.Dendritic cells transduced with full-length wild-type p53 generate antitumor cytotoxic T lymphocytes from peripheral blood of cancer patients[J].Clin Cancer Res,2001,7(1):127―135.

[48]Okada N,Masunaga Y,Okada Y,et al.Dendritic cells transduced with gp100 gene by RGD fiber-mutant adenovirus vectors are highly efficacious in generating anti-B16BL6 melanoma immunity in mice[J].Gene Ther, 2003,10(22):1891―1902.

[49]Linette G P,Shankara S,Longerich S,et al.In vitro priming with adenovirus/gp100 antigen-transduced dendritic cells reveals the epitope specificity of HLA-A* 0201-restricted CD8+T cells in patients with melanoma [J].J Immunol,2000,164(6):3402―3412.

[50]Butterfield L H,Jilani S M,Chakraborty N G,et al. Generation of melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-1 adenovirus [J].J Immunol,1998,161(10):5607―5613.

[51]Chen Y,Emtage P,Zhu Q,et al.Induction of ErbB-2/ neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells:enhanced efficacy by cotransduction of gene encoding IL-12[J].Gene Ther,2001,8(4):316―323.

[52]Wei J,Xia S,Sun H,et al.Critical role of dendritic cellderived IL-27 in antitumor immunity through regulating the recruitment and activation of NK and NKT cells[J]. Journal of immunology,2013,191(1):500―508.

[53]Lapteva N.Enhanced migration of human dendritic cells expressing inducible CD40[M].Immunotherapy of cancer.Humana Press,2010:79―87.

[54]Hopkins R A,Connolly J E.The specialized roles of immature and mature dendritic cells in antigen cross-presentation[J].Immunologic research,2012,53(1―3):91―107.

[55]Xing F,Wang J,Hu M,et al.Comparison of immature and mature bone marrow-derived dendritic cells by atomic force microscopy[J].Nanoscale research letters,2011,6 (11):455―463.

[56]Wang K L,Guo L,Shi R F,et al.Bioimmunological cha racteristics of mature or immature murine dendritic cells [J].Zhonghua yi xue za zhi,2011,91(45):3225―3228.

[57]Hodi F S,O'Day S J,McDermott D F,et al.Improved survival with ipilimumab in patients with metastatic melanoma[J].N Engl J Med,2010,363(8):711―723.

[58]Markowicz S,Nowecki Z I,Rutkowski P,et al.Adjuvant vaccination with melanoma antigen-pulsed dendritic cells in stage III melanoma patients[J].Med Oncol, 2012,29(4):2966―2977.

[責(zé)任編輯 李麥產(chǎn)]

The Research Progress of Vaccine for Dendritic Cell tumor

WANG Ying1，LI Xichun2
（1.Eɑst-City Wɑrd of Sichun Province People's Hospitɑl，Chengdu，Sichun 610101，Chinɑ；2.Chengfei Hospitɑl of Aviɑtion industry Corporɑtion of Chinɑ，Chengdu，Sichuɑn 610092，Chinɑ）

Tumor immunotherapy has been treated as an in-creasingly effective treatment for the past ten years.In recent years，a lot of research has been carried out，which on the dendritic cell vaccine of tumor vaccine.It is reviewed that the progress of tumor dendritic cell vaccine in this paper.Our purpose is to try to clear the development of the tumor vaccine for the reader.

tumor；vaccine；dendritic cell

R73

A

1672―7606(2015)04―0279―06

2015-09-12

國家自然科學(xué)基金(81402402)

汪英(1981―),女,四川成都人,醫(yī)學(xué)博士,主治醫(yī)師,從事腫瘤分子靶向治療的基礎(chǔ)與臨床研究。