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

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.