Center for Infection and Immunity, State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
PLoS One. 2011;6(9):e24407. doi: 10.1371/journal.pone.0024407. Epub 2011 Sep 9.
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.
背景：肺癌是人类最常见的恶性肿瘤，其高死亡率意味着目前尚无有效的治疗方法。因此，迫切需要开发新的肺癌治疗策略。疟疾已被报道能刺激宿主免疫反应，这被认为对某些临床癌症有效。本研究旨在提供疟原虫感染对肺癌具有治疗作用的证据。
方法/主要发现：在皮下和静脉内植入的小鼠 Lewis 肺癌（LLC）模型中，检测了疟疾感染的抗肿瘤作用。结果表明，疟疾感染抑制了 LLC 的生长和转移，并延长了荷瘤小鼠的生存时间。疟原虫感染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 TUNEL 染色增加和 Ki-67 表达减少相关。通过自然杀伤（NK）细胞细胞毒性活性、细胞因子测定、酶联免疫斑点分析、淋巴细胞增殖和流式细胞术，我们证明疟疾感染通过诱导强大的抗肿瘤固有免疫反应（包括 IFN-γ和 TNF-α的分泌和 NK 细胞的激活）以及适应性抗肿瘤免疫（增加肿瘤特异性 T 细胞增殖和 CD8+T 细胞的细胞溶解活性）来发挥抗肿瘤作用。值得注意的是，感染寄生虫的荷瘤小鼠产生了持久而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-hMUC1 的免疫反应，并且联合使用可产生协同的抗肿瘤作用。
结论/意义：疟疾感染通过在小鼠模型中诱导固有和适应性抗肿瘤反应，显著抑制 LLC 的生长。这些数据表明，疟原虫可能为肺癌免疫治疗提供一种新的策略或治疗性疫苗载体。
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