STAT3 And PD-L1 Are Negatively Regulated By ATM And Impact On The Prognosis Of Triple Negative Breast Cancer Patients With Low ATM Expression

Abstract Introduction: Triple negative breast cancer (TNBC) is known for its aggressive behaviors and lacking of effective treatment. Programmed cell death ligand-1 (PD-L1) inhibitor has just been approved for using in the management of advanced TNBC. To accurately screen TNBC sensitive to anti-PD-L1 treatment and to explore the feasibility of the ataxia-telangiectasia mutation protein (ATM) inhibitor combined with PD-L1 inhibitor, radiotherapy and chemotherapy, we focus on whether ATM participates in the regulation of PD-L1 and affects the prognosis of patients through c-Src, signal transducer and activator of transcription 1&3 (STAT1 and STAT3).Materials and methods: We used immunohistochemical staining to explore the relationship of ATM with c-Src, STAT1, STAT3, PD-1 / PD-L1, Tumor-infiltrating lymphocytes (TILs), as well as other clinicopathologic features in 86 pathological stage Ⅲ TNBCs. Their impact on prognosis was also explored. Results: We found ATM expression was negatively correlated with STAT1, STAT3, PD-L1, TILs and CD8 cells in TNBC. STAT1 up-regulates the expression of PD-L1. Only in TNBC with ATM low expression, PD-L1 was an independent negative prognostic factor, while STAT3 was an independent prognostic factor for improved prognosis. Again, only in low ATM group, the phosphorylation of tyrosine at position 419 of c-Src (p-c-src Y419) induced overexpression of STAT3.Conclusion: TNBC with low ATM expression is more likely to benefit from anti-PD-L1 inhibitors. The feasibility of ATM functional inhibitor combined with immune checkpoint blockade therapies in the treatment of TNBC is also worthy of further exploration. Our study suggests that STAT3 has different impacts on tumor progression in different tumors.