Development of a Listeria monocytogenes based vaccine against prostate cancer
Development of a Listeria monocytogenes based vaccine against prostate cancer
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DOI：
10.1007/s00262-008-0463-z
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发表时间：
2008-09-01
影响因子：
5.8
通讯作者：
Maciag, Paulo
中科院分区：
文献类型：
--
作者：
Shahabi, Vafa;Reyes-Reyes, Mariela;Maciag, Paulo
前列腺特异性抗原（PSA）是前列腺癌的可能免疫靶抗原，前列腺癌是美国男性癌症相关死亡的第二大原因。先前，我们证明了单核细胞增生李斯特菌（Lm）的减毒菌株可以用作有效的疫苗载体，用于递送肿瘤抗原，从而导致在小鼠癌症模型中建立的肿瘤消退，伴随着对这些抗原的强烈免疫应答。在本研究中，我们已经开发和鉴定了重组活减毒L。单核细胞增多症/PSA（Lm-LLO-PSA）疫苗，其具有治疗pCa的潜在用途。将人PSA基因克隆到Lm减毒株中并在其上表达。在pCa的鼠模型中测试该重组细菌疫苗Lm-LLO-PSA的稳定性、毒力、免疫原性和抗肿瘤作用。用Lm-LLO-PSA免疫显示出降低肿瘤浸润性T调节细胞的数量，并导致由表达人PSA的植入的遗传修饰的小鼠前列腺腺癌细胞系形成的超过80%的肿瘤完全消退。Lm-LLO-PSA在C57 BL/6小鼠中是免疫原性的，并且来自用Lm-LLO-PSA免疫的小鼠的脾细胞显示出响应于PSA H2 Db特异性肽的IFN-γ分泌细胞的数量显著高于幼稚动物的数量，如通过ELISpot和细胞内细胞因子染色两者所测量的。此外，使用CTL测定，我们表明，特异性PSA的T细胞能够识别和裂解PSA肽脉冲的靶细胞在体外。在与其他两种基于PSA的疫苗（pDNA和牛痘疫苗）的比较研究中，当在同源物初免/加强方案中使用时，Lm-LL 0-PSA显示出在消退已建立的肿瘤方面更有效。总之，这些结果表明，Lm-LLO-PSA是pCa免疫疗法的潜在候选者，应该进一步开发。
Prostate specific antigen (PSA) is a likely immunotherapeutic target antigen for prostate cancer, the second leading cause of cancer-related death in American men. Previously, we demonstrated that attenuated strains of Listeria monocytogenes (Lm) can be used as effective vaccine vectors for delivery of tumor antigens causing regression of established tumors accompanied by strong immune responses toward these antigens in murine models of cancer. In the present study, we have developed and characterized a recombinant live attenuated L. monocytogenes/PSA (Lm-LLO-PSA) vaccine with potential use for the treatment of pCa. Human PSA gene was cloned into and expressed by an attenuated Lm strain. This recombinant bacterial vaccine, Lm-LLO-PSA was tested for stability, virulence, immunogenicity and anti-tumor effects in a murine model for pCa. Immunization with Lm-LLO-PSA was shown to lower the number of tumor infiltrating T regulatory cells and cause complete regression of over 80% of tumors formed by an implanted genetically modified mouse prostate adenocarcinoma cell line, which expressed human PSA. Lm-LLO-PSA was immunogenic in C57BL/6 mice and splenocytes from mice immunized with Lm-LLO-PSA showed significantly higher number of IFN-gamma secreting cells over that of the naive animals in response to a PSA H2Db-specific peptide, as measured by both, ELISpot and intracellular cytokine staining. In addition, using a CTL assay we show that the T cells specific for PSA were able to recognize and lyse PSA-peptide pulsed target cells in vitro. In a comparison study with two other PSA-based vaccines (a pDNA and a vaccinia vaccine), Lm-LLO-PSA was shown to be more efficacious in regressing established tumors when used in a homologues prime/boost regimen. Together, these results indicate that Lm-LLO-PSA is a potential candidate for pCa immunotherapy and should be further developed.