鼠傷寒沙門菌(Salmonella typhimurium),，圖片來自SCIMAT/SCIENCE PHOTO LIBRARY,。
研究人員認為經(jīng)改造后表達一種細菌鞭毛蛋白(flagellin)的腫瘤細胞可能代表一種新的對抗癌癥的免疫接種策略,。鞭毛蛋白是一種已知的Toll樣受體5(toll-like receptor 5, TLR-5)的配體,，也能被Nod樣受體(Nod-like receptor, NLR)家族中兩個成員NLRC4和NAIP5(neuronal apoptisis inhibitor protein, 神經(jīng)元凋亡抑制蛋白)識別,。美國紐約市大學(xué)西奈山醫(yī)學(xué)院Julie Magarian Blander教授領(lǐng)導(dǎo)的一個研究小組證實,，一種癌細胞系改造后表達模式抗原卵清蛋白(ovalbumin, OVA)與鞭毛蛋白的融合物,，接著將這些改造后的癌細胞注射到小鼠中，然后在小鼠皮下注射活著的親代腫瘤細胞(parental tumor cell),，結(jié)果這些小鼠能夠有效地抵抗癌癥產(chǎn)生,。
重要的是，研究人員證實這種保護效應(yīng)依賴于鞭毛蛋白同時與TLR5和NLRC4/NAIP5結(jié)合：NLR結(jié)合對于小鼠產(chǎn)生持續(xù)性的T細胞抗癌免疫反應(yīng)是非常關(guān)鍵的,。研究小組就這項研究在Science Translational Medicine期刊上發(fā)表一篇題名為“Simultaneous Targeting of Toll- and Nod-Like Receptors Induces Effective Tumor-Specific Immune Responses”的論文,。
Blander博士等對一種胸腺瘤細胞系進行改造使得它能夠表達由模式抗原卵清蛋白和來自鼠傷寒沙門菌(Salmonella typhimurium)的鞭毛蛋白組成的融合蛋白。初步測試表明將這些改造過的癌細胞注射進實驗用小鼠腹腔后會觸發(fā)小鼠免疫系統(tǒng)招募嗜中性白細胞和巨噬細胞快速清除掉這些癌細胞,。這種癌細胞清除反應(yīng)特異性地依賴于TLR5信號傳導(dǎo),，但是進一步分析也顯示TLR5和NLRC4/NAIP5信號傳導(dǎo)在促使抗腫瘤CD4+ T細胞和CD8+ T細胞做好抗擊腫瘤侵入的準備和抑制腫瘤生長中發(fā)揮著同樣重要的作用。
最為關(guān)鍵的是,，當表達OVA-鞭毛蛋白的癌細胞用作疫苗時,，這些接受接種免疫的動物當遭受活著的親代腫瘤細胞攻擊時，只要TLR5和NLRC4/NAIP5識別都沒受到破壞,，就能夠成功地阻止腫瘤產(chǎn)生,。當只表達鞭毛蛋白的腫瘤細胞用來接種免疫小鼠時，研究人員也能觀察到這種保護效應(yīng)。
相反地,，用只表達OVA的癌細胞接種免疫小鼠就不能提供這種保護作用,，即便是將它們同一種重組鞭毛蛋白一起注射到小鼠中也是如此。實際上,，觸發(fā)CD4+和CD8+ T細胞免疫反應(yīng)依賴于樹突細胞對鞭毛蛋白和腫瘤抗原的關(guān)聯(lián)性識別從而使得提供給T細胞的抗原呈遞最優(yōu)化以及由此產(chǎn)生的有意義的T細胞反應(yīng),。論文作者強調(diào)，“強化的抗原呈遞主要依賴于腫瘤細胞內(nèi)實際存在的鞭毛蛋白,。”
Blander博士領(lǐng)導(dǎo)的研究小組說,，他們的發(fā)現(xiàn)提示著基于鞭毛蛋白修飾的腫瘤細胞人們可能開發(fā)出一種新的抗癌疫苗，甚至不需要整入腫瘤特異性的或外源的抗原,。
論文作者作出結(jié)論,，“我們的發(fā)現(xiàn)描繪一種誘導(dǎo)抗癌免疫反應(yīng)的新策略：將微生物結(jié)構(gòu)與TLR和NLR雙重刺激活性引入腫瘤細胞。這就確保在微生物識別的炎癥背景下識別腫瘤來演的抗原,，從而激活對抗腫瘤的天然免疫防御的胞漿途徑(cytosolic pathway)和吞噬途徑,。” (生物谷：towersimper編譯)
doi:10.1126/scitranslmed.3002868
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PMID:
Simultaneous Targeting of Toll- and Nod-Like Receptors Induces Effective Tumor-Specific Immune Responses
Johan Garaude, Andrew Kent, Nico van Rooijen and J. Magarian Blander
Toll-like receptor (TLR) ligands are increasingly being used as adjuvants in cancer vaccine trials to harness innate immunity and prime effective antitumor immune responses. Despite some success, enhancing tumor antigen presentation, promoting a protective antitumor response, and overcoming the immunosuppressive tumor microenvironment pose considerable challenges that necessitate further improvements in vaccine design. Here, we show that expression of the TLR ligand flagellin within tumor cells constitutes an effective antitumor vaccination strategy that relies on simultaneous engagement of TLR5 and the Nod-like receptors (NLRs) NLRC4/NAIP5 (neuronal apoptosis inhibitory protein 5) by flagellin along with associative recognition of tumor antigen for optimal antigen presentation to T cells. Although TLR5 signaling was critical for mediating rapid macrophage-dependent clearance of flagellin-expressing tumor cells in vivo, TLR5 and NLRC4/NAIP5 were equally important for priming antitumor CD4+ and CD8+ T cells and suppressing tumor growth. Vaccination with irradiated flagellin-expressing tumor cells prevented tumor development, and disrupting flagellin recognition by TLR5 or NLRC4/NAIP5 impaired protective immunization against an existing or subsequent tumor. Our findings delineate a new strategy to induce anticancer immune responses consisting of introducing microbial structures with dual TLR and NLR stimulatory activity into tumor cells. This ensures recognition of tumor-derived antigen within the inflammatory context of microbial recognition and additionally activates both the phagocytic and the cytosolic pathways of innate immune defense against the tumor
