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Immune reaction with tumor-infiltrating lymphocytes (TILs) has been extensively investigated in breast cancer. Programmed cell death 1 and its ligand (PD-L1) are key physiologic suppressors of cytotoxic immune reaction. However, the combination of TILs with PD-L1 expression has not been well studied in breast cancer.A multi-color immunohistochemical multiplex assay simultaneously detecting PD-L1, CD8, and CD163 was performed on biopsy whole sections from 123 HER2-positive (HER2+) breast cancers, including 64 treated with anti-HER2 neoadjuvant therapy and subsequent resection.PD-L1 expression was identified in 88 cases (72%) including 21 (17%) in tumor cells and 67 (55%) in immune cells. PD-L1 expression was positively associated with high Nottingham grade, high nuclear grade, and a high level of CD8+ and CD163+ cells. Among the 64 patients who received neoadjuvant therapy, 39 had pathologic complete remission (pCR) and 25 had incomplete response. Multivariate analysis showed progesterone receptor negativity, HER2/chromosome 17 centromere (CEN17) ratio and intratumoral CD8+ cells were significantly associated with pCR. Furthermore, all patients with intratumoral CD8+ cells but no PD-L1 expression achieved pCR.Our data have shown that examination of intratumoral CD8+ cells together with PD-L1 expression proves useful in predicting response to anti-HER2 targeted therapy in patients with HER2+ breast cancer.