Abstract
BackgroundAlthough 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.MethodsIn 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.ResultsIn 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.ConclusionOur results indicated that PPP2R2B could serve as a promising biomarker for TNBC, and help predict immunotherapeutic response and guide personalized strategies in TNBC treatment.
Highlights
Immune checkpoint blockade has emerged as a novel promising strategy for triplenegative breast cancer (TNBC), many patients fail response or acquire resistance to current agents
We focused on CD8 T cells due to its central role in immune surveillance and immunotherapy
To better identify TNBC-specific biomarker associated with CD8 T cells infiltration, we performed Weighted gene correlation network analysis (WGCNA) to obtain the crucial module highly related to CD8 T cells infiltration (Fig. 2b–c; Additional file 6: Figure S2a)
Summary
Immune checkpoint blockade has emerged as a novel promising strategy for triplenegative breast cancer (TNBC), many patients fail response or acquire resistance to current agents. Li et al Cancer Cell Int (2021) 21:13 the adjuvant treatment has improved in recent years, the treatment of TNBC is still up against several challenges owing to the absent expression of targetable receptors and heterogeneous clinical behavior [3]. Immunotherapy have represented a promising therapeutic strategy for several cancer types, including breast cancer [4,5,6]. Compared to other breast cancer subtypes, TNBC could harbor greater potential in immunotherapy due to higher levels of tumor infiltrating lymphocytes (TILs), programmed death-ligand protein (PD-L1), and nonsynonymous mutations [7, 8]. The recurrence and metastasis of TNBC are frequently facilitated by immune evasion, which is partly due to the restriction of anti-tumor immunity derived by T-lymphocyte in the tumor microenvironment [9]
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