Intratumoral Injection with ＂Listeria monocytogenes＂ Provides Anticancer Effects in a Subcutaneous Liver Tumor Model

目的：臨床上無法產生有效的抗腫瘤免疫反應，通常是因為腫瘤抗原無法被免疫系統所認識，因此增加腫瘤抗原被免疫細胞所辨識，將可有效改善腫瘤的免疫治療。近幾年有些研究利用厭氧菌或兼性厭氧菌注射到腫瘤細胞內，誘發發炎反應藉此達成腫瘤抗原被免疫細胞所辨識，產生一個有效的抗腫瘤免疫反應來達到治療腫瘤的效果，本研究是要利用李斯特菌感染肝癌細胞，透過腫瘤細胞內注射李斯特菌，藉此誘發肝癌細胞內的抗腫瘤免疫反應，來達到治療腫瘤的目的。方法與結果：將肝癌細胞株（BNL 1MEA.7R.1）和李斯特菌同時注射到小鼠（BALB/c）皮下，來觀察腫瘤的生長情形，結果發現在實驗的老鼠中都沒有腫瘤產生，直到第70天在老鼠另一側皮下再次注射肝癌細胞株，仍然不會有腫瘤產生，相反的，只注射肝癌細胞株的老鼠，在注射完後14天內皮下全都產生腫瘤。進一步我們利用李斯特菌進行腫瘤治療實驗，結果發現低劑量的李斯特菌能夠有效抑制皮下腫瘤生長，高劑量的李斯特菌治療效果更明顯。利用免疫組織化學染色來分析治療後的腫瘤細胞內免疫細胞內的浸潤情形，結果顯示以李斯特菌治療的腫瘤內顆粒球細胞、CD4^+和CD8^+ T細胞數目明顯增加，分析腫瘤細胞中細胞凋亡的數量也會明顯增加。結論：實驗結果顯示利用李斯特菌注射在腫瘤細胞內能誘發老鼠產生一個全身性、長效性的抗腫瘤免疫反應，並且能有效的治療腫瘤。本研究結果提供了在腫瘤內注射李斯特菌為一個具潛力的肝癌治療方法。

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Objectives: A major obstacle for the development of effective immunotherapy is the ability of tumors to escape the immune system. The possibility to kill tumor cells because they are recognized as infected rather than as malignant could help overcome immune escape mechanisms. Some anaerobic and facultative anaerobic bacteria represent novel therapeutic agents that have been recently applied in cancer therapy. In this study, we investigated the antitumor activity of Listeria monocytogenes in the murine BNL 1MEA.7R.1 subcutaneous hepatocellular carcinoma (HCC) model. The antitumor effects of L. monocytogenes were evaluated in mice bearing subcutaneous tumors. Methods and Results: Co-injection of BNL 1MEA.7R.1 cells and L. monocytogenes into syngeneic BALB/c mice elicited protective immunity in the animals, which could inhibit the growth of parental tumor cells reinjection. The antitumor immunity induced by intratumoral treatment by L. monocytogenes significantly reduced the growth of preestablished subcutaneous tumors. However, the therapeutic effects were less prominent in the mice inoculated with a large tumor load or in mice treated later. Immunohistochemical staining of the tumors revealed increased infiltration of neutrophils, CD4+ and CD8+ T cells in tumor microenvironment following L. monocytogenes treatment. TUNEL assay of the tumors revealed that L. monocytogenes treatment significantly increased the number of apoptotic cells in the tumor regions. Conclusion: These results suggest that ＂L. monocytogenes＂, exert an indirect toxic effect on tumor cells through the recruitment of inflammatory cells and the cross-presentation of tumor antigens, which allow induction of tumor-specific immune response. This research suggests that intratumoral injection with ＂L. monocytogenes＂ which represents a potential strategy for the treatment of HCC.

並列關鍵字

＂Listeria monocytogenes＂； Hepatocellular Carcinoma

國際替代計量

Intratumoral Injection with ＂Listeria monocytogenes＂ Provides Anticancer Effects in a Subcutaneous Liver Tumor Model

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