背景:尽管免疫检查点阻断已成为三阴性乳腺癌(TNBC)的一种新的有希望的策略,许多患者对目前的药物反应失败或获得抵抗。因此,我们的重点需要转向替代抑制靶点,反应性的预测因子,和免疫抑制机制。
方法:在本研究中,我们进行了系统的生物信息学分析,以确定PPP2R2B在TNBC中是一种强大的肿瘤抑制因子.同时,乳腺癌进展细胞系模型应用于我们的研究.进行定量实时PCR测定(Q-PCR)以评估PPP2R2B在乳腺癌发作和进展中的作用。此外,我们通过基于巨噬细胞的体外实验验证了PPP2R2B对免疫活性的影响.为了进一步解读PPP2R2B在TNBC中的作用,我们研究了转录组水平,基因组概况,及其临床预后价值。
结果:在TNBC组织中,与正常乳腺组织相比,PPP2R2B表达显著下调。Kaplan-Meier生存分析显示,PPP2R2B低表达患者的生存时间比PPP2R2B高表达患者的生存时间短。Q-PCR分析表明,PPP2R2B下调可能在乳腺癌的发生和发展中起关键作用。此外,我们的研究结果表明,PPP2R2B与CD8T细胞呈正相关,CD4Th1辅助细胞,和M1巨噬细胞,但与M2巨噬细胞呈负相关。随后的结果确定PPP2R2B与免疫抑制剂基因(GZMA,PRF1和IFNG),能改善T淋巴细胞的抗肿瘤功能,抑制免疫逃避。同时,在低PPP2R2B表达组中,T细胞受体信号通路和抗原加工和呈递信号通路被显著抑制。之后,基于PPP2R2B表达的不同亚组在体细胞突变中表现出几个独特的特征,副本编号更改,拷贝数负担的程度,和启动子甲基化水平。
结论:我们的结果表明,PPP2R2B可以作为TNBC的有希望的生物标志物,并帮助预测免疫治疗反应并指导TNBC治疗的个性化策略。
BACKGROUND: Although immune checkpoint blockade has emerged as a novel promising strategy for triple-negative breast cancer (TNBC), many patients fail response or acquire resistance to current agents. Consequently, our focus need to shift toward alternative inhibitory targets, predictor for responsiveness, and immune suppressive mechanisms.
METHODS: In this study, we performed systematic bioinformatics analyses to identify
PPP2R2B as a robust tumor suppressor in TNBC. Meanwhile, breast cancer progression cell line model was applied in our research. Quantitative real-time PCR assay (Q-PCR) was carried out to assess the role of
PPP2R2B in the onset and progression of breast cancer. Furthermore, we validated the effect of
PPP2R2B on immune activity via in vitro experiments based on macrophages. To further decipher the roles of PPP2R2B in TNBC, we investigated the transcriptome level, genomic profiles, and its clinical prognostic value.
RESULTS: In TNBC tissues, PPP2R2B expression was significantly downregulated compared to normal breast tissues. Kaplan-Meier survival analysis revealed that patients with low
PPP2R2B expression had shorter survival time than those with high
PPP2R2B expression. Q-PCR analysis suggested that PPP2R2B downregulation could play a key role in breast-cancer initiation and progression. Additionally, our findings showed that PPP2R2B was positively related with CD8 T cells, CD4 Th1 helper cells, and M1 macrophages, but negatively related with M2 macrophages. Subsequent results identified that PPP2R2B was strongly related with immune inhibitor genes (GZMA, PRF1, and IFNG), which could improve T lymphocytes antitumor function and restrict immune evasion. Meanwhile, T cell receptor signaling pathway and antigen processing and presentation signaling pathway were significantly suppressed in low PPP2R2B expression group. Afterwards, distinct subgroups based on PPP2R2B expression exhibited several unique features in somatic mutations, copy numbers alterations, extent of copy number burden, and promoter methylation level.
CONCLUSIONS: Our results indicated that PPP2R2B could serve as a promising biomarker for TNBC, and help predict immunotherapeutic response and guide personalized strategies in TNBC treatment.