Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis.
A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies.



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.



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).



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.
Department of Oncology, Military Institute of Medicine, Szaserów St 128, 04-141, Warsaw, Poland. rdtt@wp.pl.
Renata
R
Duchnowska
Department of Pathology, Medical University of Gdańsk, 7 Dębinki St, 80-211, Gdańsk, Poland.
Rafał
R
Pęksa
Department of Oncology, Regional Oncology Center, 66a Katowicka St, 45-060, Opole, Poland.
Barbara
B
Radecka
Department of Neurosurgery, Oncology Center-Institute, 5 Roentgena St, 02-781, Warsaw, Poland.
Tomasz
T
Mandat
Department of Neurosurgery, Medical University of Lublin, 1 Al. Racławickie, 20-059, Lublin, Poland.
Tomasz
T
Trojanowski
Department of Neurosurgery, Medical University of Lublin, 1 Al. Racławickie, 20-059, Lublin, Poland.
Bożena
B
Jarosz
Department of Oncology, Regional Oncology Center, 12 Ogrodowa St, 15-027, Białystok, Poland.
Bogumiła
B
Czartoryska-Arłukowicz
Department of Pathology, Oncology Center-Institute, 5 Roentgena St, 02-781, Warsaw, Poland.
Wojciech P
WP
Olszewski
Department of Neurosurgery, Regional Hospital, 18 Żołnierska St, 10-561, Olsztyn, Poland.
Waldemar
W
Och
Department of Oncology, Regional Oncology Center, 62 Pabianicka St, 93-513, Łódź, Poland.
Ewa
E
Kalinka-Warzocha
Department of Pathology, Military Institute of Medicine, Szaserów St 128, 04-141, Warsaw, Poland.
Wojciech
W
Kozłowski
Department of Oncology and Radiotherapy, Medical University of Gdańsk, 7 Dębinki St, 80-211, Gdańsk, Poland.
Anna
A
Kowalczyk
Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, East Melbourne, VIC, 8006, Australia.
Sherene
S
Loi
Department of Pathology, Medical University of Gdańsk, 7 Dębinki St, 80-211, Gdańsk, Poland.
Wojciech
W
Biernat
Department of Oncology and Radiotherapy, Medical University of Gdańsk, 7 Dębinki St, 80-211, Gdańsk, Poland.
Jacek
J
Jassem
D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D003131:Combined Modality Therapy; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060787:Neoplasm Grading; D010641:Phenotype; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D016016:Proportional Hazards Models; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*
D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D061026:Programmed Cell Death 1 Receptor
Brain metastases; Breast cancer; Lymphocytes; PD-1; PD-L