PPP2R2B downregulation is associated with immune evasion and predicts poor clinical outcomes in triple-negative breast cancer

Abstract

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. Conclusion 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.

Integrated analysis identifies a novel lncRNA prognostic signature associated with aerobic glycolysis and hub pathways in breast cancer

“…Weighted Gene Correlation Network Analysis procedure was carried out as described previously. 26 Briefly, a soft thresholding power of six was selected to generate a scale‐free topology from adjacency matrix. DeepSplit of 2 and minModuleSize of 30 were set as the parameters of the Dynamic Tree Cut method to avoid generating too many modules.…”

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

“…It was shown that the antigen processing and presentation were weakened in the PPP2R2B low tumor cells. Thus, the measures to avoid PPP2R2B loss might be investigated to retain the more benign phenotype of cancer [ 170 ].…”

Identification and Validation of a Novel Prognostic Model Based on Platinum Resistance-Related Genes in Bladder Cancer

“…Downregulation of PPP2R2B reduces the effect of trastuzumab or lapatinib on mTOR signaling, thus weaken the anti-HER2 sensitivity 42 . What is more, PPP2R2B also involves in polarization of macrophages, the dysregulation of PPP2R2B would promote macrophages polarizing to M2, facilitating the immune evasion 43 . TSPAN7 inhibits the expression of E-cadherin and vimentin, which raises the level of N-cadherin44.…”