PDF(Pubmed)
Abstract：
The lack of effective treatment options for an increasing number of cancer cases highlights the need for new anticancer therapeutic strategies. Immunotherapy mediated by Salmonella enterica Typhimurium is a promising anticancer treatment. Candidate strains for anticancer therapy must be attenuated while retaining their antitumor activity. Here, we investigated the attenuation and antitumor efficacy of two S. enterica Typhimurium mutants, ΔtolRA and ΔihfABpmi, in a murine melanoma model. Results showed high attenuation of ΔtolRA in the Galleria mellonella model, and invasion and survival in tumor cells. However, it showed weak antitumor effects in vitro and in vivo. Contrastingly, lower attenuation of the attenuated ΔihfABpmi strain resulted in regression of tumor mass in all mice, approximately 6 days after the first treatment. The therapeutic response induced by ΔihfABpmi was accompanied with macrophage accumulation of antitumor phenotype (M1) and significant increase in the mRNAs of proinflammatory mediators (TNF-α, IL-6, and iNOS) and an apoptosis inducer (Bax). Our findings indicate that the attenuated ΔihfABpmi exerts its antitumor activity by inducing macrophage infiltration or reprogramming the immunosuppressed tumor microenvironment to an activated state, suggesting that attenuated S. enterica Typhimurium strains based on nucleoid-associated protein genes deletion could be immunotherapeutic against cancer.
摘要：
越来越多的癌症病例缺乏有效的治疗选择，这凸显了对新抗癌治疗策略的需求。由鼠伤寒沙门氏菌介导的免疫治疗是一种有前途的抗癌治疗方法。抗癌治疗的候选菌株必须减毒，同时保留其抗肿瘤活性。这里,我们研究了两种鼠伤寒沙门氏菌突变体的减毒和抗肿瘤功效，ΔtolRA和ΔihfABpmi，在小鼠黑色素瘤模型中。结果显示在Galleriamellonella模型中ΔtolRA的高度衰减，以及肿瘤细胞的侵袭和存活。然而,它在体外和体内表现出微弱的抗肿瘤作用。相反，减弱的ΔihfABpmi菌株的较低衰减导致所有小鼠的肿瘤质量消退，第一次治疗后约6天。ΔihfABpmi诱导的治疗反应伴随着巨噬细胞积累的抗肿瘤表型（M1）和促炎介质的mRNA显着增加（TNF-α，IL-6和iNOS）和凋亡诱导剂（Bax）。我们的发现表明，减弱的ΔihfABpmi通过诱导巨噬细胞浸润或将免疫抑制的肿瘤微环境重编程为激活状态来发挥其抗肿瘤活性，提示以类核相关蛋白基因缺失为基础的减毒鼠伤寒沙门氏菌菌株可能对癌症具有免疫治疗作用。
