Strategy for eliciting antigen-specific CD8+T cell-mediated immune response against a cryptic CTL epitope of merkel cell polyomavirus large T antigen
Strategy for eliciting antigen-specific CD8+T cell-mediated immune response against a cryptic CTL epitope of merkel cell polyomavirus large T antigen
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DOI：
10.1186/2045-3701-2-36
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发表时间：
2012-10-24
影响因子：
7.5
通讯作者：
Hung, Chien-Fu
中科院分区：
文献类型：
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作者：
Gomez, Bianca P.;Wang, Connie;Hung, Chien-Fu
背景：默克尔细胞癌（MCC）是一个相对较新的肿瘤病毒引起的癌症不断扩大的类别。虽然仍然罕见，但近年来病例数量急剧上升。使这一趋势进一步复杂化的是，MCC是一种极具侵袭性的肿瘤，患者预后不良，晚期疾病的治疗选择有限。MCC的病原体已被确定为默克尔细胞多瘤病毒（MCPyV）。MCPyV编码的大T（LT）抗原是一种癌蛋白，理论上认为其对于病毒介导的肿瘤发生是必需的，因此是用于产生抗肿瘤免疫应答的优良MCC抗原。作为外源抗原，LT癌蛋白避免了免疫耐受的障碍，而免疫耐受通常阻碍抗肿瘤免疫的发展。因此，它是抗MCC免疫疗法的极好靶标。由于肿瘤特异性CD 8 + T细胞导致MCC和许多其他癌症的更好预后，我们已经产生了能够引发LT特异性CD 8 + T细胞的DNA疫苗。DNA疫苗（pcDNA 3-CRT/LT）编码的LT抗原与一种损伤相关的分子模式钙网蛋白（CRT）相连，因为已经证明CRT与抗原的连接促进了抗原特异性CD 8 + T细胞的诱导。这是相关的，因为pcDNA 3-CRT/LT DNA疫苗的治疗效果是由LT特异性CD 8 + T细胞介导的。用DNA疫苗接种的小鼠明显产生更多的LT特异性CD 8 + T细胞。该DNA疫苗还能够赋予LT特异性CD 8 + T细胞介导的保护和治疗作用，以延长具有LT表达肿瘤的小鼠的生存期。为了确定MCC特异性CD 8 + T细胞识别的LT表位，我们鉴定了免疫显性LT表位的氨基酸序列aa 19 -27（IAPNCYGNI），并发现其为H-2k（B）-restricted.Conclusion：本研究的结果可以促进MCC治疗的其他模式的发展，如基于肽的疫苗和LT特异性CD 8 + T细胞的过继转移。同样，MCC DNA疫苗具有很大的临床转化潜力，因为其免疫特异性高，并且治疗策略可以用于解决其他病毒诱导的肿瘤。
Background: Merkel cell carcinoma (MCC) is a relatively new addition to the expanding category of oncovirus-induced cancers. Although still comparably rare, the number of cases has risen dramatically in recent years. Further complicating this trend is that MCC is an extremely aggressive neoplasm with poor patient prognosis and limited treatment options for advanced disease. The causative agent of MCC has been identified as the merkel cell polyomavirus (MCPyV). The MCPyV-encoded large T (LT) antigen is an oncoprotein that is theorized to be essential for virus-mediated tumorigenesis and is therefore, an excellent MCC antigen for the generation of antitumor immune responses. As a foreign antigen, the LT oncoprotein avoids the obstacle of immune tolerance, which normally impedes the development of antitumor immunity. Ergo, it is an excellent target for anti-MCC immunotherapy. Since tumor-specific CD8+ T cells lead to better prognosis for MCC and numerous other cancers, we have generated a DNA vaccine that is capable of eliciting LT-specific CD8+ T cells. The DNA vaccine (pcDNA3-CRT/LT) encodes the LT antigen linked to a damage-associated molecular pattern, calreticulin (CRT), as it has been demonstrated that the linkage of CRT to antigens promotes the induction of antigen-specific CD8+ T cells.Results: The present study shows that DNA vaccine-induced generation of LT-specific CD8+ T cells is augmented by linking CRT to the LT antigen. This is relevant since the therapeutic effects of the pcDNA3-CRT/LT DNA vaccine is mediated by LT-specific CD8+ T cells. Mice vaccinated with the DNA vaccine produced demonstrably more LT-specific CD8+ T cells. The DNA vaccine was also able to confer LT-specific CD8+ T cell-mediated protective and therapeutic effects to prolong the survival of mice with LT-expressing tumors. In the interest of determining the LT epitope which most MCC-specific CD8+ T cells recognize, we identified the amino acid sequence of the immunodominant LT epitope as aa19-27 (IAPNCYGNI) and found that it is H-2k(b)-restricted.Conclusion: The results of this study can facilitate the development of other modes of MCC treatment such as peptide-based vaccines and adoptive transfer of LT-specific CD8+ T cells. Likewise, the MCC DNA vaccine has great potential for clinical translation as the immunologic specificity is high and the treatment strategy can be exported to address other virus-induced tumors.