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Purpose: High level of tumor-infiltrating lymphocytes (TILs) can predict the rate of total pathological complete remission (tpCR) of breast cancer patients who receive neoadjuvant chemotherapy (NACT). This study focused on evaluating the data of patients whose primary tumor and/or lymph node metastasis show nonresponse (NR) to NACT, trying to provide a basis for the clinical decision which patients will develop NACT resistance. Methods: The study included breast cancers from 991 patients who received NACT. ROC curve was used to analyze the predictive value of TILs for tpCR and NR in breast cancer with different molecular subtypes. Multivariate logistic regression was used to assess the association of various factors, particularly the TILs, with the possibility of tpCR and NR. Spearman’s rank correlation coefficient was used to analyze the relationship between TILs and routine pathological indices.Results: ROC curve analysis confirmed that TILs showed significant predictive value for NR of HR + HER2 - and TNBC. When TILs at a cutoff of 10% and 17.5%, the sum of sensitivity and specificity reaches the maximum in HR + HER2- and TNBC respectively. Among HR+HER2− breast cancer, TILs≥ 10% was an independent predictor for low NR rate. Furthermore, positive correlation of TILs with Ki67 index and Miller-Payne grade, and negative correlation with ER and PR H-scores were only identified in this subgroup. In TNBC, TILs ≥17.5% was an independent predictor for low NR rate. Conclusions: The predictive value of low TILs on NR may facilitate to screen patients with HR+HER2- or TNBC who may not benefit from NACT. The study is also suggestive that patients with HR+HER2− cancer with low TILs infiltration may benefit more from other neoadjuvant regimes such as endocrine therapy. Further studies are required to validate these findings.

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.