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Background  A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies.    Methods  Immunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD-L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment.    Results  Median survival after BCBM excision was 18.3 months (range 0–99). Median number of CD4+, CD8+ TILs and CD68+ was 49, 69 and 76 per 1 mm 2 , respectively. PD-L1 and PD-L2 expression in BCBM was present in 53 % and 36 % of cases, and was not related to BCBM phenotype. PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs ( r  = 0.26 and 0.33), and so did CD68+ ( r  = 0.23 and 0.27, respectively). In the multivariate analysis, survival after BCBM excision positively correlated with PD-1 expression on TILs (hazard ratio (HR) = 0.3,  P  = 0.003), CD68+ infiltration (HR = 0.2,  P  < 0.001), brain radiotherapy (HR = 0.1,  P  < 0.001), endocrine therapy (HR = 0.1,  P  < 0.001), and negatively with hormone-receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive phenotype of primary tumor (HR = 2.6,  P  = 0.01), HER2 expression in BCBM (HR = 4.9,  P  = 0.01).    Conclusions  PD-L1 and PD-L2 expression is a common occurrence in BCBM, irrespective of primary tumor and BCBM phenotype. Favorable prognostic impact of PD-1 expression on TILs suggests a beneficial effect of preexisting immunity and implies a potential therapeutic role of immune checkpoint inhibitors in BCBM.

Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis