上世紀(jì)90年代初,，加利福尼亞州斯坦福大學(xué)醫(yī)學(xué)院的免疫學(xué)家埃德加?恩格爾曼宣布他發(fā)現(xiàn)了一種疫苗,，能利用人體的免疫細(xì)胞來(lái)治療癌癥，并表示在幾年內(nèi)他將開(kāi)發(fā)出可以投入使用的癌癥疫苗,。自此后，癌癥疫苗作為一種新的癌癥治療策略一度燃起了癌癥患者及其家庭對(duì)于疾病治療的希望。然而,，在過(guò)去的20年癌癥疫苗的發(fā)展之路卻并未能如人們當(dāng)初希望那樣順暢。其中的一個(gè)巨大挑戰(zhàn)就是科學(xué)家們尚無(wú)法找到既可終止癌癥生長(zhǎng)又不會(huì)抑制免疫系統(tǒng)的細(xì)胞靶點(diǎn),。
近日來(lái)自北卡羅來(lái)納大學(xué)Lineberger綜合癌癥中心的科學(xué)家們稱(chēng)他們的實(shí)驗(yàn)發(fā)現(xiàn)有希望能夠提高癌癥疫苗的療效,。研究人員證實(shí)敲除NLRP3蛋白可使腫瘤對(duì)治療性癌癥疫苗的反應(yīng)增強(qiáng)四倍。相關(guān)論文發(fā)表在2010年12月15日的Cancer Research雜志上,。
論文的作者Jonathan Serody說(shuō)：“這一研究結(jié)果表明NLRP3在疫苗的開(kāi)發(fā)中可起到意想不到的作用,，為我們提供了一個(gè)有潛力的藥物靶點(diǎn)提高疫苗的效力。”
該研究工作由北卡羅來(lái)納大學(xué)Lineberger免疫學(xué)計(jì)劃的兩位負(fù)責(zé)人：腫瘤免疫學(xué)專(zhuān)家Serod博士和NLR蛋白家族研究領(lǐng)域的先驅(qū)Jenny Ting共同領(lǐng)導(dǎo),。Serody是北卡羅來(lái)納大學(xué)血液學(xué)和腫瘤學(xué)系的教授,。Ting是北卡羅來(lái)納大學(xué)微生物學(xué)和免疫學(xué)系教授、炎癥研究中心的負(fù)責(zé)人,。
研究人員證實(shí)敲除NLRP3蛋白可抑制腫瘤相關(guān)的髓樣抑制細(xì)胞的作用,，使得達(dá)到腫瘤生長(zhǎng)位點(diǎn)的髓樣抑制細(xì)胞降低了五倍。在過(guò)去的研究中Serody和同事們?cè)C實(shí)這些骨髓細(xì)胞在腫瘤逃逸免疫反應(yīng)中發(fā)揮了極其重要的作用,。新研究發(fā)現(xiàn)是第一次將髓樣抑制細(xì)胞,、NLRP3蛋白與癌癥疫苗反應(yīng)聯(lián)系起來(lái)。
Serody說(shuō)：“我們本以為NLRP3蛋白失活會(huì)降低免疫系統(tǒng)對(duì)癌癥的反應(yīng)能力,。過(guò)去的研究表明NLRP3在抗腫瘤免疫應(yīng)答中發(fā)揮著決定性的作用,。然而我們的研究發(fā)現(xiàn)當(dāng)這些蛋白失活時(shí)，癌癥疫苗會(huì)變得更為有效,。這是因?yàn)镹LRP3蛋白失活使得髓樣抑制細(xì)胞無(wú)法到達(dá)腫瘤位點(diǎn)促進(jìn)腫瘤生長(zhǎng)和降低疫苗的效力,。”
盡管研究人員一直致力于開(kāi)發(fā)出有效的癌癥疫苗，但是到目前為止只有Dendreon公司研發(fā)的Provenge被美國(guó)FDA批準(zhǔn)成為首個(gè)上市的治療性疫苗,，主要針對(duì)晚期前列腺癌患者,。Provenge被證實(shí)能夠?qū)⒒颊叩纳嫫谘娱L(zhǎng)3-4個(gè)月。
疫苗的制造非常的困難,。由于疫苗具有個(gè)體特異性,，需要通過(guò)個(gè)體免疫細(xì)胞產(chǎn)生，因而疫苗的生產(chǎn)過(guò)程要求必須首先從患者體內(nèi)分離出免疫細(xì)胞,，然后將其運(yùn)送至公司再生成特異的疫苗,。這使得疫苗的價(jià)格非常的昂貴。Provenge用于三次治療的花費(fèi)大約是在10萬(wàn)美元,。
“癌癥疫苗無(wú)法像藥片一樣進(jìn)行批量生產(chǎn),，”Serody解釋說(shuō)：“此外，它也不同于對(duì)抗病毒的疫苗例如脊髓灰質(zhì)炎疫苗和天花疫苗。癌細(xì)胞有時(shí)候會(huì)‘欺騙’我們的身體,，將它視為我們身體內(nèi)的正常細(xì)胞,，從而逃避機(jī)體的免疫系統(tǒng)。我們希望我們的研究將推動(dòng)開(kāi)發(fā)出更有效的疫苗對(duì)抗多種癌癥類(lèi)型,。”（生物谷Bioon.com）
生物谷推薦原文出處：
Cancer Res. doi: 10.1158/0008-5472.CAN-10-1921
The Inflammasome Component Nlrp3 Impairs Antitumor Vaccine by Enhancing the Accumulation of Tumor-Associated Myeloid-Derived Suppressor Cells
Hendrik W. van Deventer1, Joseph E. Burgents2, Qing Ping Wu3, Rita-Marie T. Woodford4, W. June Brickey2,3, Irving C. Allen2, Erin McElvania-Tekippe2, Jonathan S. Serody1,2,3, and Jenny P.-Y. Ting2,3,4
Abstract
The inflammasome is a proteolysis complex that generates the active forms of the proinflammatory cytokines interleukin (IL)-1β and IL-18. Inflammasome activation is mediated by NLR proteins that respond to microbial and nonmicrobial stimuli. Among NLRs, NLRP3 senses the widest array of stimuli and enhances adaptive immunity. However, its role in antitumor immunity is unknown. Therefore, we evaluated the function of the NLRP3 inflammasome in the immune response using dendritic cell vaccination against the poorly immunogenic melanoma cell line B16-F10. Vaccination of Nlrp3?/? mice led to a relative 4-fold improvement in survival relative to control animals. Immunity depended on CD8+ T cells and exhibited immune specificity and memory. Increased vaccine efficacy in Nlrp3?/? hosts did not reflect differences in dendritic cells but rather differences in myeloid-derived suppressor cells (MDSC). Although Nlrp3 was expressed in MDSCs, the absence of Nlrp3 did not alter either their functional capacity to inhibit T cells or their presence in peripheral lymphoid tissues. Instead, the absence of Nlrp3 caused a 5-fold reduction in the number of tumor-associated MDSCs found in host mice. Adoptive transfer experiments also showed that Nlrp3?/? MDSCs were less efficient in reaching the tumor site. Depleting MDSCs with an anti–Gr-1 antibody increased the survival of tumor-bearing wild-type mice but not Nlrp3?/? mice. We concluded that Nlrp3 was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T-cell immunity after dendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumor immune responses, suggesting novel approaches to improve the response to antitumor vaccines by limiting Nlrp3 signaling.
