2012年11月14日訊 /生物谷BIOON/ 近日，由北京大學(xué)醫(yī)學(xué)部免疫學(xué)系的研究人員和美國(guó)貝勒醫(yī)學(xué)院合作,，在篩選腫瘤特異抗原方面取得重要成果。最新代表性研究論文于近日在線發(fā)表在《癌癥研究》（Cancer Research）上,。
腫瘤特異抗原（Tumor-specific antigen, TSA）具有在正常組織低表達(dá),，而在腫瘤組織中高表達(dá)的特點(diǎn)，對(duì)腫瘤的早期診斷和腫瘤免疫治療都十分關(guān)鍵,。部分腫瘤特異抗原被證明能有效誘導(dǎo)體內(nèi)免疫應(yīng)答,，在腫瘤疫苗的研制中有重要價(jià)值。
篩選腫瘤特異抗原的傳統(tǒng)方法包括抑制性刪減雜交（SSH）和重組cDNA表達(dá)文庫(kù)的血清學(xué)分析（SEREX）等,，實(shí)驗(yàn)周期較長(zhǎng),，且成本偏高。該研究團(tuán)隊(duì)首先采用生物信息學(xué)策略篩選腫瘤特異抗原,，通過(guò)分析在臨床上已經(jīng)得到認(rèn)可的腫瘤特異抗原的表達(dá)譜特點(diǎn),，開(kāi)發(fā)出一套獨(dú)特的算法HEPA（heterogeneous expression profile analysis），能有效從基因組中篩選出腫瘤中高表達(dá)的基因,，并用實(shí)驗(yàn)方法進(jìn)行驗(yàn)證,，初步得到19個(gè)腫瘤特異抗原。研究人員隨后開(kāi)發(fā)了一種新的篩選血清中抗體的方法PARSE (Protein A/G based reverse serum ELISA) ,，用以檢測(cè)腫瘤患者血清中針對(duì)腫瘤特異抗原的自身特異性抗體,。通過(guò)PARSE方法，研究人員發(fā)現(xiàn)在4~11的肺癌患者血清中,，有針對(duì)四個(gè)新腫瘤抗原的自身特異性抗體,，而在健康人血清中罕見(jiàn)。在兩組獨(dú)立的肺癌病人血清中,，四種自身特異性抗體的聯(lián)合ROC曲線下面積均達(dá)0.71以上,，提示可以作為診斷肺癌的聯(lián)合標(biāo)志物。
該研究提供了從分析腫瘤特異抗原表達(dá)譜特點(diǎn)入手,，開(kāi)發(fā)信息學(xué)算法快速篩選腫瘤特異抗原,，到表達(dá)譜驗(yàn)證，檢測(cè)腫瘤患者體液免疫反應(yīng)陽(yáng)性率,，再到腫瘤標(biāo)志物聯(lián)合診斷的一套完整思路,，對(duì)腫瘤的早期診斷和腫瘤疫苗的研制都具有重要參考價(jià)值。(生物谷Bioon.com)
doi:10.1158/0008-5472.CAN-12-1656
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An integrated genome-wide approach to discover tumor specific antigens as potential immunological and clinical targets in cancer
Tumor-specific antigens (TSAs) are central elements in the immune control of cancers. To systematically explore the TSA genome, we developed a computational technology called Heterogeneous Expression Profile Analysis (HEPA), which can identify genes relatively uniquely expressed in cancer cells in contrast to normal somatic tissues. Rating human genes by their HEPA score enriched for clinically useful TSA genes, nominating candidate targets whose tumor-specific expression was verified by RT-PCR. Coupled with HEPA, we designed a novel assay termed Protein A/G based Reverse Serological Evaluation (PARSE) for quick detection of serum autoantibodies against an array of putative TSA genes. Remarkably, highly tumor-specific autoantibody responses against seven candidate targets were detected in 4-11 of patients, resulting in distinctive autoantibody signatures in lung and stomach cancers. Interrogation of a larger cohort of 149 patients and 123 healthy individuals validated the predictive value of the autoantibody signature for lung cancer. Together, our results establish an integrated technology to uncover a cancer-specific antigen genome offering a reservoir of novel immunological and clinical targets.
