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In vitro Treatment of a Murine Mammary Adenocarcinoma Cell Line with Recombinant Trypanosoma cruzi Calreticulin Promotes Immunogenicity and Phagocytosis.
Molecular Immunology ( IF 3.2 ) Pub Date : 2020-06-08 , DOI: 10.1016/j.molimm.2020.05.013
Eduardo Sosoniuk-Roche 1 , Pamela Cruz 1 , Ismael Maldonado 1 , Leonora Duaso 1 , Bárbara Pesce 2 , Marek Michalak 3 , Carolina Valck 4 , Arturo Ferreira 1
Affiliation  

American Trypanosomiasis, a parasitic disease produced by Trypanosoma cruzi (T. cruzi), endemic in Latin America, infects about 6 million people. During the chronic stage of the infection, approximately 30% of infected people will develop Chagas Disease, the clinical manifestation. Few decades ago it was reported that, during the chronic stage, the parasite interferes with the development of solid tumors. However, the identification of parasite molecules responsible for such effects remained elusive. Years later, we described T.cruzi Calreticulin (TcCalr), an endoplasmic reticulum resident chaperone that infective trypomastigotes translocate to the parasite exterior, where it displays anticomplement activities. Most likely, at least some of these activities are related with the antitumor properties of TcCalr, as shown in in vitro, ex vivo, in ovum, and in vivo models. In this context we, we have seen that in vivo subcutaneous peritumoral inoculation of rTcCalr enhances local infiltration of T cells and slows tumor development. Based on these precedents, we propose that in vitro treatment of a mammary adenocarcinoma (TA3 cell line) with rTcCalr, will enhance tumor immunogenicity. In agreement with this proposal, we have shown that: i). rTcCalr binds to TA3 cells in a concentration-dependent fashion, ii). C1q binds to TA3 cells in an rTcCalr-dependent fashion, confirmed by the reversion attained using anti-TcS (a central TcCalr domain that binds C1) F(ab’)2 antibody fragments, iii). incubation of TA3 cells with rTcCalr, promotes cell phagocytosis by murine macrophages and, iv). rTcCalr decreases the membrane expression of MHC class II, m-Dectin-1, Galectin-9 and PD-L1, while increasing the expression of Rae-1γ. In synthesis, herein we show that in vitro treatment of a murine mammary adenocarcinoma with rTcCalr enhances phagocytosis and modulates the expression of a variety of membrane molecules that correlates with increased tumor immunogenicity.



中文翻译:

重组克氏锥虫钙网蛋白对小鼠乳腺腺癌细胞的体外治疗可促进免疫原性和吞噬作用。

美国锥虫病是一种由拉丁美洲流行的锥虫锥虫T. cruzi)产生的寄生虫病,感染了约600万人。在感染的慢性阶段,大约30%的感染者会发展出恰加斯病,这是临床表现。几十年前,有报道说,在慢性阶段,寄生虫会干扰实体瘤的发展。然而,鉴定造成这种作用的寄生虫分子仍然是难以捉摸的。几年后,我们描述了克鲁斯钙网蛋白(TcCalr)是一种内质网常驻分子伴侣,具有感染力的锥虫病易位至寄生虫的外部,在其中表现出抗补体活性。最有可能的是,这些活性中的至少一些与TcCalr的抗肿瘤特性有关,如体外离体,卵子体内模型所示。在这种情况下,我们已经看到,rTcCalr的体内皮下肿瘤周围接种可增强T细胞的局部浸润并减慢肿瘤的发展。基于这些先例,我们建议在体外用rTcCalr治疗乳腺腺癌(TA3细胞系)将增强肿瘤的免疫原性。同意该建议,我们表明:i)。rTcCalr以浓度依赖的方式与TA3细胞结合,ii)。C1q以rTcCalr依赖的方式与TA3细胞结合,这通过使用抗TcS(结合C1的中央TcCalr域)F(ab')2抗体片段获得的逆转得到证实,iii)。用rTcCalr孵育TA3细胞,可促进小鼠巨噬细胞吞噬细胞,iv)。rTcCalr降低II类MHC,m-Dectin-1,Galectin-9和PD-L1的膜表达,同时增加Rae-1γ的表达。在合成中,本文显示了体外 用rTcCalr治疗鼠乳腺腺癌可增强吞噬作用,并调节与提高的肿瘤免疫原性相关的各种膜分子的表达。

更新日期:2020-06-08
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