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Cancer Cell International
Published in: Cancer Cell International 1/2021

Open Access 01-12-2021 | Breast Cancer | Primary research

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

Authors: Zheng Li, Yaming Li, Xiaolong Wang, Qifeng Yang

Published in: Cancer Cell International | Issue 1/2021

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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.
Appendix
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Literature
1.
Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova K, Leversha M, Hogg N, Seshan VE, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell. 2012;150(1):165–78.PubMedPubMedCentralCrossRef
2.
Keren L, Bosse M, Marquez D, Angoshtari R, Jain S, Varma S, Yang SR, Kurian A, Van Valen D, West R, et al. A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell. 2018;174(6):1373-1387.e1319.PubMedPubMedCentralCrossRef
3.
Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13(11):674–90.PubMedPubMedCentralCrossRef
4.
Stevanović S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, Dudley ME, Yang JC, Sherry RM, Kammula US, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33(14):1543–50.PubMedPubMedCentralCrossRef
5.
6.
7.
Jia H, Truica CI, Wang B, Wang Y, Ren X, Harvey HA, Song J, Yang JM. Immunotherapy for triple-negative breast cancer: Existing challenges and exciting prospects. Drug Resist Updat. 2017;32:1–15.PubMedCrossRef
8.
Keenan TE, Tolaney SM. Role of immunotherapy in triple-negative breast cancer. J Natl Compr Cancer Netw. 2020;18(4):479–89.CrossRef
9.
Li ZL, Zhang HL, Huang Y, Huang JH, Sun P, Zhou NN, Chen YH, Mai J, Wang Y, Yu Y, et al. Autophagy deficiency promotes triple-negative breast cancer resistance to T cell-mediated cytotoxicity by blocking tenascin-C degradation. Nat Commun . 2020;11(1):3806.PubMedPubMedCentralCrossRef
10.
Shifrut E, Carnevale J, Tobin V, Roth TL, Woo JM, Bui CT, Li PJ, Diolaiti ME, Ashworth A, Marson A. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell. 2018;175(7):1958-1971.e1915.PubMedPubMedCentralCrossRef
11.
de la Rojo Vega M, Chapman E, Zhang DD. NRF2 and the hallmarks of cancer. Cancer Cell. 2018;34(1):21–43.CrossRef
12.
Zhang L, Romero P. Metabolic control of CD8(+) T cell fate decisions and antitumor immunity. Trends Mol Med. 2018;24(1):30–48.PubMedCrossRef
13.
Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, Araki K, Ahmed R. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev Med. 2018;69:301–18.PubMedCrossRef
14.
Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J, Meng Q, Yu X, Shi S. Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol. 2020;13(1):110.PubMedPubMedCentralCrossRef
15.
Laheurte C, Dosset M, Vernerey D, Boullerot L, Gaugler B, Gravelin E, Kaulek V, Jacquin M, Cuche L, Eberst G, et al. Distinct prognostic value of circulating anti-telomerase CD4(+) Th1 immunity and exhausted PD-1(+)/TIM-3(+) T cells in lung cancer. Br J Cancer. 2019;121(5):405–16.PubMedPubMedCentralCrossRef
16.
17.
Zhao H, Li D, Zhang B, Qi Y, Diao Y, Zhen Y, Shu X. PP2A as the main node of therapeutic strategies and resistance reversal in triple-negative breast cancer. Molecules (Basel, Switzerland). 2017;22(12):2277.CrossRef
18.
Eitelhuber AC, Warth S, Schimmack G, Düwel M, Hadian K, Demski K, Beisker W, Shinohara H, Kurosaki T, Heissmeyer V, et al. Dephosphorylation of Carma1 by PP2A negatively regulates T-cell activation. The EMBO journal. 2011;30(3):594–605.PubMedCrossRef
19.
Tan J, Lee PL, Li Z, Jiang X, Lim YC, Hooi SC, Yu Q. B55β-associated PP2A complex controls PDK1-directed myc signaling and modulates rapamycin sensitivity in colorectal cancer. Cancer Cell. 2010;18(5):459–71.PubMedCrossRef
20.
Madera-Salcedo IK, Sánchez-Hernández BE, Svyryd Y, Esquivel-Velázquez M, Rodríguez-Rodríguez N, Trejo-Zambrano MI, García-González HB, Hernández-Molina G, Mutchinick OM, Alcocer-Varela J, et al. PPP2R2B hypermethylation causes acquired apoptosis deficiency in systemic autoimmune diseases. JCI insight. 2019;5(16):e126457.CrossRef
21.
Álvarez-Fernández M, Sanz-Flores M, Sanz-Castillo B, Salazar-Roa M, Partida D, Zapatero-Solana E, Ali H, Manchado E, Lowe S, VanArsdale T, et al. Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer. Cell Death Differ. 2018;25(5):828–40.PubMed
22.
Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, Castiglioni I, et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2016;44(8):e71.PubMedCrossRef
23.
Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC20 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12(4):R41.PubMedPubMedCentralCrossRef
24.
Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747–56.PubMedPubMedCentralCrossRef
25.
Tian Y, Morris TJ, Webster AP, Yang Z, Beck S, Feber A, Teschendorff AE. ChAMP: updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics (Oxford, England). 2017;33(24):3982–4.CrossRef
26.
27.
28.
Sveen A, Ågesen TH, Nesbakken A, Meling GI, Rognum TO, Liestøl K, Skotheim RI, Lothe RA. ColoGuidePro: a prognostic 7-gene expression signature for stage III colorectal cancer patients. Clin Cancer Res . 2012;18(21):6001–10.PubMedCrossRef
29.
30.
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7.PubMedPubMedCentralCrossRef
31.
Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, et al. The immune landscape of cancer. Immunity. 2018;48(4):812-830.e814.PubMedPubMedCentralCrossRef
32.
33.
Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, et al. The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.PubMedPubMedCentralCrossRef
34.
Guenthoer J, Diede SJ, Tanaka H, Chai X, Hsu L, Tapscott SJ, Porter PL. Assessment of palindromes as platforms for DNA amplification in breast cancer. Genome Res. 2012;22(2):232–45.PubMedPubMedCentralCrossRef
35.
Orsetti B, Nugoli M, Cervera N, Lasorsa L, Chuchana P, Rougé C, Ursule L, Nguyen C, Bibeau F, Rodriguez C, et al. Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q. Br J Cancer. 2006;95(10):1439–47.PubMedPubMedCentralCrossRef
36.
37.
Huang H, Sikora MJ, Islam S, Chowdhury RR, Chien YH, Scriba TJ, Davis MM, Steinmetz LM. Select sequencing of clonally expanded CD8(+) T cells reveals limits to clonal expansion. Proc Natl Acad Sci USA. 2019;116(18):8995–9001.PubMedCrossRefPubMedCentral
38.
Kansy BA, Shayan G, Jie HB, Gibson SP, Lei YL, Brandau S, Lang S, Schmitt NC, Ding F, Lin Y, et al. T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response. Oncoimmunology. 2018;7(11):e1494112.PubMedPubMedCentralCrossRef
39.
Desrichard A, Snyder A, Chan TA. Cancer neoantigens and applications for immunotherapy. Clin Cancer Res . 2016;22(4):807–12.PubMedCrossRef
40.
Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1–2):48–61.PubMedPubMedCentralCrossRef
41.
Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, Holt RA. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014;24(5):743–50.PubMedPubMedCentralCrossRef
42.
Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, Chu MF, Hodgson K, Berger T, Wakeham A, et al. Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1. Proc Natl Acad Sci USA. 2019;116(10):4326–35.PubMedCrossRefPubMedCentral
43.
Zhang X, Kim S, Hundal J, Herndon JM, Li S, Petti AA, Soysal SD, Li L, McLellan MD, Hoog J, et al. Breast cancer neoantigens can induce CD8(+) T-cell responses and antitumor immunity. Cancer Immunol Res. 2017;5(7):516–23.PubMedPubMedCentralCrossRef
44.
Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science. 2017;355(6322):eaaf8399.PubMedPubMedCentralCrossRef
45.
46.
Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara H, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185-s198.PubMedCrossRef
47.
48.
Reuben A, Gittelman R, Gao J, Zhang J, Yusko EC, Wu CJ, Emerson R, Zhang J, Tipton C, Li J, et al. TCR Repertoire intratumor heterogeneity in localized lung adenocarcinomas: an association with predicted neoantigen heterogeneity and postsurgical recurrence. Cancer Discov. 2017;7(10):1088–97.PubMedPubMedCentralCrossRef
49.
Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, et al. CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol. 2018;36(28):2836–44.PubMedPubMedCentralCrossRef
50.
51.
Peranzoni E, Lemoine J, Vimeux L, Feuillet V, Barrin S, Kantari-Mimoun C, Bercovici N, Guérin M, Biton J, Ouakrim H, et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc Natl Acad Sci USA. 2018;115(17):E4041-e4050.PubMedCrossRefPubMedCentral
52.
Malfitano AM, Pisanti S, Napolitano F, Di Somma S, Martinelli R, Portella G. Tumor-associated macrophage status in cancer treatment. Cancers. 2020;12(7):1987.PubMedCentralCrossRef
53.
Saha D, Martuza RL, Rabkin SD. Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell. 2017;32(2):253-267.e255.PubMedPubMedCentralCrossRef
54.
Pereira B, Chin SF, Rueda OM, Vollan HK, Provenzano E, Bardwell HA, Pugh M, Jones L, Russell R, Sammut SJ, et al. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat Commun . 2016;7:11479.PubMedPubMedCentralCrossRef
55.
56.
57.
Jia Q, Wang J, He N, He J, Zhu B. Titin mutation associated with responsiveness to checkpoint blockades in solid tumors. JCI Insight. 2019;4(10):e127901.PubMedCentralCrossRef
58.
Tao Y, Liu S, Briones V, Geiman TM, Muegge K. Treatment of breast cancer cells with DNA demethylating agents leads to a release of Pol II stalling at genes with DNA-hypermethylated regions upstream of TSS. Nucleic Acids Res. 2011;39(22):9508–20.PubMedPubMedCentralCrossRef
59.
Muggerud AA, Rønneberg JA, Wärnberg F, Botling J, Busato F, Jovanovic J, Solvang H, Bukholm I, Børresen-Dale AL, Kristensen VN, et al. Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer. Breast Cancer Res. 2010;12(1):R3.PubMedPubMedCentralCrossRef
Metadata
Title
PPP2R2B downregulation is associated with immune evasion and predicts poor clinical outcomes in triple-negative breast cancer
Authors
Zheng Li
Yaming Li
Xiaolong Wang
Qifeng Yang
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01707-9

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