Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity
Antitumor Effect of Malaria Parasite Infection in a Murine Lewis Lung Cancer Model through Induction of Innate and Adaptive Immunity
复制标题
疟疾寄生虫感染在小鼠路易斯肺癌模型中通过诱导先天和适应性免疫的抗肿瘤作用
DOI：
10.1371/journal.pone.0024407
复制
发表时间：
2011-09-09
期刊：
影响因子：
3.7
通讯作者：
Chen, Xiaoping
中科院分区：
文献类型：
--
作者：
Chen, Lili;He, Zhengxiang;Chen, Xiaoping
背景肺癌是人类最常见的恶性肿瘤，其高病死率意味着没有有效的治疗方法。因此，迫切需要开发新的肺癌治疗策略。据报道，疟疾可刺激宿主免疫应答，这被认为可有效地对抗某些临床癌症。这项研究旨在提供证据，疟疾寄生虫感染是治疗肺癌。方法/主要发现在皮下和静脉植入的小鼠刘易斯肺癌（LLC）模型中检查疟疾感染的抗肿瘤作用。结果表明，疟疾感染可抑制LLC的生长和转移，延长荷瘤小鼠的生存期。对感染疟疾的小鼠肿瘤的组织学分析显示，血管生成受到抑制，这与肿瘤中末端脱氧核苷酸转移酶介导的（TUNEL）染色增加和Ki-67表达降低相关。通过自然杀伤（NK）细胞的细胞毒性活性、细胞因子测定、酶联免疫斑点测定、淋巴细胞增殖和流式细胞术，我们证明疟疾感染通过诱导有效的抗肿瘤先天免疫应答，包括IFN-γ和TNF-α的分泌和NK细胞的活化以及随着肿瘤特异性T细胞的增加而产生的适应性抗肿瘤免疫。CD 8 + T细胞的细胞增殖和细胞溶解活性。值得注意的是，感染寄生虫的荷瘤小鼠产生了持久有效的肿瘤特异性免疫。因此，我们发现疟原虫感染可以增强肺癌DNA疫苗pcDNA3.1-hMUC 1的免疫应答，二者联合产生协同抗肿瘤作用。结论/意义在小鼠模型中，疟疾感染通过诱导先天性和适应性抗肿瘤反应显著抑制LLC生长。这些数据表明，疟原虫可能为抗肺癌免疫治疗提供新的策略或治疗性疫苗载体。
Background Lung cancer is the most common malignancy in humans and its high fatality means that no effective treatment is available. Developing new therapeutic strategies for lung cancer is urgently needed. Malaria has been reported to stimulate host immune responses, which are believed to be efficacious for combating some clinical cancers. This study is aimed to provide evidence that malaria parasite infection is therapeutic for lung cancer. Methodology/Principal Findings Antitumor effect of malaria infection was examined in both subcutaneously and intravenously implanted murine Lewis lung cancer (LLC) model. The results showed that malaria infection inhibited LLC growth and metastasis and prolonged the survival of tumor-bearing mice. Histological analysis of tumors from mice infected with malaria revealed that angiogenesis was inhibited, which correlated with increased terminal deoxynucleotidyl transferase-mediated (TUNEL) staining and decreased Ki-67 expression in tumors. Through natural killer (NK) cell cytotoxicity activity, cytokine assays, enzyme-linked immunospot assay, lymphocyte proliferation, and flow cytometry, we demonstrated that malaria infection provided anti-tumor effects by inducing both a potent anti-tumor innate immune response, including the secretion of IFN-γ and TNF-α and the activation of NK cells as well as adaptive anti-tumor immunity with increasing tumor-specific T-cell proliferation and cytolytic activity of CD8+ T cells. Notably, tumor-bearing mice infected with the parasite developed long-lasting and effective tumor-specific immunity. Consequently, we found that malaria parasite infection could enhance the immune response of lung cancer DNA vaccine pcDNA3.1-hMUC1 and the combination produced a synergistic antitumor effect. Conclusions/Significance Malaria infection significantly suppresses LLC growth via induction of innate and adaptive antitumor responses in a mouse model. These data suggest that the malaria parasite may provide a novel strategy or therapeutic vaccine vector for anti-lung cancer immune-based therapy.