Skip to main content

Advertisement

SpringerLink
Log in

Syntenin1/MDA-9 (SDCBP) induces immune evasion in triple-negative breast cancer by upregulating PD-L1

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Syntenin1/SDCBP (syndecan binding protein), also known as melanoma differentiation associated gene-9 (MDA-9), is a PDZ domain-containing molecule, which was initially identified as a key oncogene in melanoma. However, the role of syntenin1 in triple-negative breast cancer (TNBC), especially in suppression of antitumour immune response, remains unknown.

Methods and Results

One hundred TNBC tissues were obtained after radical resection and used for analysis. High syntenin1 expression was associated with increased tumour size (r = 0.421, P < 0.001), presence of lymph node metastasis (r = 0.221, P = 0.044) and poor overall survival (P = 0.01) and recurrence-free survival (P = 0.007). Syntenin1 overexpression significantly promoted 4T1 tumour growth and lung metastasis in BALB/c mice by affecting CD8+ T cells. Western blot and flow cytometry analyses demonstrated that syntenin1 induced CD8+ T cell apoptosis in vitro and in vivo through upregulating PD-L1. Western blot demonstrated that syntenin1 upregulated PD-L1 expression by inducing Tyr705 stat3 phosphorylation, which was further confirmed by stat3 inhibition study. The correlation between syntenin1 and PD-L1 was further confirmed using tumour tissues derived from patients with TNBC (r = 0.509, P < 0.001). Efficacy studies indicated that 4T1-scramble tumour benefitted from anti-PD-L1 therapy (P < 0.001); however, 4T1-syntenin1-KD demonstrated no response to anti-PD-L1 treatment (P = 0.076).

Conclusions

Syntenin1 exhibits a profound function in mediating T cells apoptosis by upregulating PD-L1 and thus could be used as a prognostic biomarker of TNBC. Tumoural syntenin1 expression corelated with anti-PD-L1 treatment efficacy. Targeting syntenin1-mediated T-cell suppression could be a potential strategy for improving the prognosis of patients with TNBC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Khosravi-Shahi P, Cabezon-Gutierrez L, Custodio-Cabello S (2018) Metastatic triple negative breast cancer: Optimizing treatment options, new and emerging targeted therapies. Asia Pac J Clin Oncol 14(1):32–39

    Article  PubMed  Google Scholar 

  2. Collignon J, Lousberg L, Schroeder H, Jerusalem G (2016) Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer (Dove Med Press) 8:93–107

    CAS  Google Scholar 

  3. Li X, Yang J, Peng L, Sahin AA, Huo L, Ward KC, O’Regan R, Torres MA, Meisel JL (2017) Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer. Breast Cancer Res Treat 161(2):279–287

    Article  PubMed  Google Scholar 

  4. Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ (2017) Pd-L1. J Clin Pathol 71(3):189–194

    Article  PubMed  Google Scholar 

  5. Polk A, Svane IM, Andersson M, Nielsen D (2017) Checkpoint inhibitors in breast cancer—current status. Cancer Treat Rev 63:122–134

    Article  PubMed  CAS  Google Scholar 

  6. Jelinek T, Mihalyova J, Kascak M, Duras J, Hajek R (2017) PD-1/PD-L1 inhibitors in haematological malignancies: update 2017. Immunology 152(3):357–371

    Article  PubMed  CAS  Google Scholar 

  7. Gong J, Chehrazi-Raffle A, Reddi S, Salgia R (2018) Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 6(1):8

    Article  PubMed  PubMed Central  Google Scholar 

  8. Polk A, Svane IM, Andersson M, Nielsen D (2018) Checkpoint inhibitors in breast cancer—current status. Cancer Treat Rev 63:122–134

    Article  PubMed  CAS  Google Scholar 

  9. Lin JJ, Jiang H, Fisher PB (1998) Melanoma differentiation associated gene-9, mda-9, is a human gamma interferon responsive gene. Gene 207(2):105–110

    Article  PubMed  CAS  Google Scholar 

  10. Boukerche H, Su ZZ, Prevot C, Sarkar D, Fisher PB (2008) mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src. Proc Natl Acad Sci U S A 105(41):15914–15919

    Article  PubMed  PubMed Central  Google Scholar 

  11. Das SK, Bhutia SK, Kegelman TP, Peachy L, Oyesanya RA, Dasgupta S, Sokhi UK, Azab B, Dash R, Quinn BA et al (2012) MDA-9/syntenin: a positive gatekeeper of melanoma metastasis. Front Biosci (Landmark Ed) 17:1–15

    Article  CAS  Google Scholar 

  12. Das SK, Bhutia SK, Sokhi UK, Azab B, Su ZZ, Boukerche H, Anwar T, Moen EL, Chatterjee D, Pellecchia M et al (2012) Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma. Cancer Res 72(23):6217–6226

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Katz H, Alsharedi M (2017) Immunotherapy in triple-negative breast cancer. Med Oncol 35(1):13

    Article  PubMed  CAS  Google Scholar 

  15. Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, Boccia R, Lippman ME, Somer R, Smakal M et al (2017) Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN solid tumor study. Breast Cancer Res Treat 167(3):671–686

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD et al (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34(21):2460–2467

    Article  PubMed  CAS  Google Scholar 

  17. Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, Freeman GJ, Ferris RL (2016) Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNgamma that induce PD-L1 expression in head and neck cancer. Cancer Res 76(5):1031–1043

    Article  PubMed  CAS  Google Scholar 

  18. Kumar S, Davra V, A EO, Geng K, T LW, Birge RB (2017) Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer. Oncoimmunology 7(1):e1376155

    Article  PubMed  PubMed Central  Google Scholar 

  19. Janse van Rensburg HJ, Azad T, Ling M, Hao Y, Snetsinger B, Khanal P, Minassian LM, Graham CH, Rauh MJ, Yang X: The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Res 2018

  20. Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, Wang HY, Wysocka M, Cheng M, Ruggeri BA et al (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A 105(52):20852–20857

    Article  PubMed  PubMed Central  Google Scholar 

  21. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V, Chouaib S (2014) PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211(5):781–790

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kashyap R, Roucourt B, Lembo F, Fares J, Carcavilla AM, Restouin A, Zimmermann P, Ghossoub R (2015) Syntenin controls migration, growth, proliferation, and cell cycle progression in cancer cells. Front Pharmacol 6:241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Cui L, Cheng S, Liu X, Messadi D, Yang Y, Hu S (2016) Syntenin-1 is a promoter and prognostic marker of head and neck squamous cell carcinoma invasion and metastasis. Oncotarget 7(50):82634–82647

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zhong D, Ran JH, Tang WY, Zhang XD, Tan Y, Chen GJ, Li XS, Yan Y (2012) Mda-9/syntenin promotes human brain glioma migration through focal adhesion kinase (FAK)-JNK and FAK-AKT signaling. Asian Pac J Cancer Prev 13(6):2897–2901

    Article  PubMed  Google Scholar 

  25. Dasgupta S, Menezes ME, Das SK, Emdad L, Janjic A, Bhatia S, Mukhopadhyay ND, Shao C, Sarkar D, Fisher PB (2013) Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling. Clin Cancer Res 19(17):4621–4633

    Article  PubMed  CAS  Google Scholar 

  26. Poma P, Labbozzetta M, D’Alessandro N, Notarbartolo M (2017) NF-kappaB Is a potential molecular drug target in triple-negative breast cancers. OMICS 21(4):225–231

    Article  PubMed  CAS  Google Scholar 

  27. Yang Y, Hong Q, Shi P, Liu Z, Luo J, Shao Z (2013) Elevated expression of syntenin in breast cancer is correlated with lymph node metastasis and poor patient survival. Breast Cancer Res 15(3):R50

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Qian XL, Li YQ, Yu B, Gu F, Liu FF, Li WD, Zhang XM, Fu L (2013) Syndecan binding protein (SDCBP) is overexpressed in estrogen receptor negative breast cancers, and is a potential promoter for tumor proliferation. PLoS One 8(3):e60046

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Qian XL, Zhang J, Li PZ, Lang RG, Li WD, Sun H, Liu FF, Guo XJ, Gu F, Fu L (2017) Dasatinib inhibits c-src phosphorylation and prevents the proliferation of triple-negative breast cancer (TNBC) cells which overexpress syndecan-binding protein (SDCBP). PLoS One 12(1):e0171169

    Article  PubMed  PubMed Central  Google Scholar 

  30. Liu X, Zhang X, Lv Y, Xiang J, Shi J (2014) Overexpression of syntenin enhances hepatoma cell proliferation and invasion: potential roles in human hepatoma. Oncol Rep 32(6):2810–2816

    Article  PubMed  CAS  Google Scholar 

  31. Foley K, Kim V, Jaffee E, Zheng L (2016) Current progress in immunotherapy for pancreatic cancer. Cancer Lett 381(1):244–251

    Article  PubMed  CAS  Google Scholar 

  32. Stier S, Totzke G, Grunewald E, Neuhaus T, Fronhoffs S, Sachinidis A, Vetter H, Schulze-Osthoff K, Ko Y (2000) Identification of syntenin and other TNF-inducible genes in human umbilical arterial endothelial cells by suppression subtractive hybridization. FEBS Lett 467(2–3):299–304

    Article  PubMed  CAS  Google Scholar 

  33. Li N, Wang J, Zhang N, Zhuang M, Zong Z, Zou J, Li G, Wang X, Zhou H, Zhang L et al (2018) Cross-talk between TNF-alpha and IFN-gamma signaling in induction of B7-H1 expression in hepatocellular carcinoma cells. Cancer Immunol Immunother 67(2):271–283

    Article  PubMed  CAS  Google Scholar 

  34. Hartley G, Regan D, Guth A, Dow S (2017) Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-alpha. Cancer Immunol Immunother 66(4):523–535

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

The Science &Technology Development Fund of Tianjin Education Commission for Higher Education. (2017KJ198); The Foundation of Tianjin Medical University (2016KYZQ17).

Author information

Author notes

  1. Jing Liu, Yanfang Yang, Hongwei Wang and Bin Wang shared co-first authorship.

Authors and Affiliations

  1. Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Huan-Hu-Xi Road Ti-Yuan-Bei, Hexi District, Tianjin, 300060, China

    Jing Liu, Yanfang Yang, Jun Liu & Jian Yin

  2. Tianjin Medical University, Ministry of Education, Tianjin, 300060, China

    Hongwei Wang, Kaili Zhao & Weiwei Bai

  3. College of Management and Economics, Tianjin University, Tianjin, 300072, China

    Bin Wang

  4. Department of Laboratory Medicine, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China

    Wenna Jiang

Authors
  1. Jing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanfang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongwei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaili Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenna Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiwei Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jian Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jing Liu, Jun Liu or Jian Yin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 KB)

Supplementary Fig1

. (a)Syntenin1 protein expression analysis of 4T1-scramble and 4T1-syntenin1-KD by western blotting. 4T1-scramble and 4T1-syntenin1-KD were used for further mouse tumour models. (b) Statistical analysis of the percentage of tumour-infiltrating CD45+ cells. (c) Immunocompromised BABL/c nude mice were inoculated with 4T1-scramble or 4T1-syntenin1-KD in parallel with those immunocompetent WT BABL/c mice. Tumour volumes were measured every 3 days from day 7 to 34 after inoculation. Tumour growth curves for 4T1-scramble groups and 4T1-syntenin1-KD groups were shown. (n=7 per group) * in black P&#x003C;0.05 by repeated measure two-way ANOVA, (time × tumour volume, main effect of group), * in blue P&#x003C;0.05, ** in blue P&#x003C;0.01, by one-way ANOVA followed by Bonferroni post-hoc analysis for each time points.(d) The comparison of tumour volume inhibiting rate after syntenin1 knocked down in WT BABL/c mice and in nude mice. *P&#x003C;0.05 by paired Student’s t-test. (TIF 3115 KB)

Supplementary Fig2

. Tumour volumes of 4T1-scramble and 4T1-syntenin1-KD in immunocompetent WT BABL/c mice after receiving CD8+ cells depletion or isotype IgG. (n=10 per group) Results from one-way ANOVA followed by Bonferroni post-hoc analysis for each time points. * P&#x003C;0.05, ** P&#x003C;0.01, ***P&#x003C;0.001 n.s.: not significant. (TIF 4450 KB)

Supplementary Fig3

. (a) Statistical analysis of IFNγ secretion. Isolated CD8+T cells were co-cultured with MDA-MB-231-vector, MDA-MB-231-syntenin1, MDA-MB-231-scramble, MDA-MB-231-syntenin1-KD for 48h. ELISA was used to evaluate the concentration of IFNγ in the medium. (b) Statistical analysis of the percentage of activated caspase-3+CD8+T cells. Isolated CD8+T cells were co-cultured with MDA-MB-231-vector, MDA-MB-231-syntenin1, MDA-MB-231-scramble, MDA-MB-231-syntenin1-KD for 12h. Activated caspase-3 and CD8 were labelled and tested by flowcytometry. (c) CFSE dilution of CD8+T cells after 3 days co-cultured with MDA-MB-231-vector, MDA-MB-231-syntenin1, MDA-MB-231-scramble, MDA-MB-231-syntenin1-KD. Proportion of divided CD8+T cells were analysed. *P&#x003C;0.05, **P&#x003C;0.01, by paired Student’s t-test (a, b, c) (TIF 5683 KB)

Supplementary Fig4

. Western blot band intensities of syntenin1, PD-L1, P-stat3, t-stat3 relative to β-tubulin were analyzed between groups:(a,c) Statistical analysis of the band intensities ratio between TNBC-vector and TNBC-syntenin1.(b,d) Statistical analysis of the band intensities ratio between TNBC-scramble and TNBC-syntenin1-KD. (TIF 4172 KB)

Supplementary Fig5

. Tumour volumes of 4T1-scramble and 4T1-syntenin1-KD in immunocompetent WT BABL/c mice after receiving anti-PD-L1 treatment or isotype IgG. (n=7 per group) Results from one-way ANOVA followed by Bonferroni post-hoc analysis for each time points. ** P&#x003C;0.01, ***P&#x003C;0.001 n.s.: not significant. (TIF 4265 KB)

Supplementary Fig6

. Statistical analysis of the percentage of tumour-infiltrating CD45+ cells by one-way ANOVA. (TIF 1473 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J., Yang, Y., Wang, H. et al. Syntenin1/MDA-9 (SDCBP) induces immune evasion in triple-negative breast cancer by upregulating PD-L1. Breast Cancer Res Treat 171, 345–357 (2018). https://doi.org/10.1007/s10549-018-4833-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-018-4833-8

Keywords

Search

Navigation