MHSP65-TCL疫苗对不同病理类型三阴性乳腺癌治疗效果的差异

Efficacy differences of MHSP65-TCL vaccine in the treatment of triple-negative breast cancer of different pathological types

目的评估及比较改良后的结核分枝杆菌热休克蛋白65-肿瘤细胞裂解物(MHSP65-TCL)疫苗对不同类型三阴性乳腺癌的疗效和差异。方法首先,生物信息学分析不同病理类型三阴性乳腺癌肿瘤微环境中免疫细胞浸润活化情况;其次,分析三阴性乳腺癌细胞中RACK1、Bcl-2、CTNNBL1等细胞活化因子,及细胞凋亡诱导因子PDL1、HMGB1、Fas-L在三阴性乳腺细胞中的丰度及其影响免疫细胞活化的信号通路。进而,在制备MHSP65-TCL去除TCL中的PDL1或增加TCL中Bcl-2,再通过体内外抗肿瘤实验,检测、比较两种方法治疗不同类型三阴性乳腺癌效果的差异。结果蛋白表达丰度的检测,MDA-MB-453细胞中HMGB1的表达量是最高的,但Bcl-2表达最低,结合各类型三阴性乳腺癌淋巴浸润,体外杀伤实验以及体内动物实验,3种不同类型的三阴性乳腺癌细胞尤其是LAR型细胞系MDA-MB-453,主要依赖HMGB1抑制免疫细胞。从TCL中去除HMGB1可以更为有效地提高MHSP65-TCL的抗肿瘤效果。结论阐明MHSP65-TCL疫苗对各类型三阴性乳腺癌疗效差异及机制,并建立起一种三阴性乳腺癌治疗的新方法。

Objective To evaluate and compare the efficacy and differences of the MHSP65-TCL(modified mycobacterium tuberculosis heat-shock protein 65 tumor cell lysate)vaccine for different types of triple-negative breast cancer.Methods Firstly,bioinformatics was used to analyse immune cell infiltration and activation in the tumor microenvironment of different pathological types of triple-negative breast cancer.Secondly,this study analyzed the abundance of cell-activating factors such as RACK1,Bcl-2,CTNNBL1,and apoptosis-inducing factors PDL1,HMGB1,Fas-L in triple-negative breast cancer cells and their signaling pathways affecting immune cell activation.Then,we prepared MHSP65-TCL to remove PDL1 from TCL or to increase Bcl-2 in TCL,and then tested and compared the effects of these two methods in treating different types of triple-negative breast cancer through in vivo and in vitro anti-tumor assays.Results The expression of HMGB1 was the highest in MDA-MB-453 cells,but the expression of Bcl-2 was the lowest.Combined with lymphatic invasion of various types of triple-negative breast cancer,in vitro killing assays and in vivo animal experiments,three different types of triple-negative breast cancer cells,(especially the LAR cell line MDA-MB-453)mainly relied on HMGB1 to suppress immune cells.Removal of HMGB1 from TCL could improve the anti-tumor effect of MHSP65-TCL more effectively.Conclusion This study elucidates the difference in efficacy and mechanism of MHSP65-TCL vaccine on each type of triple-negative breast cancer,and establishes a new method for the treatment of triple-negative breast cancer.