title: The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer.
abstract: Programmed death 1 (PD-1) is a co-inhibitory receptor in the CD28/CTL-4 family, and functions as a negative regulator of the immune system. Tumor-infiltrating lymphocytes (TIL) in many epithelial cancers express PD-1, suggesting that antitumor immunity may be modulated by the PD-1/PD-L1 signaling pathway, and promising results from two recent clinical trials with monoclonal antibodies targeting PD-1 or PD-L1 confirm the clinical relevance of this pathway in human cancer. To explore the role of PD-1(+) TIL in human breast cancer, we performed immunohistochemistry studies on a tissue microarray encompassing 660 breast cancer cases with detailed clinical annotation and outcomes data. PD-1(+) TIL were present in 104 (15.8 %) of the 660 breast cancer cases. Their presence was associated with tumor size, grade, and lymph node status, and was differentially associated with the intrinsic subtypes of breast cancer. In univariate survival analyses, the presence of PD-1(+) TIL was associated with a significantly worse overall survival (HR = 2.736, p < 0.001). In subset analyses, the presence of PD-1(+) TIL was associated with significantly worse overall survival in the luminal B HER2(-) subtype (HR = 2.678, p < 0.001), the luminal B HER2(+) subtype (HR = 3.689, p < 0.001), and the basal-like subtype (HR = 3.140, p < 0.001). This is the first study to demonstrate that the presence of PD-1(+) TIL is associated with poor prognosis in human breast cancer, with important implications for the potential application of antibody therapies targeting the PD-1/PD-L1 signaling pathway in this disease.
authors.affiliation: Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, Basel 4031, Switzerland. muensts@uhbs.ch
authors.forename: S
authors.initials: S
authors.lastname: Muenst
authors.forename: S D
authors.initials: SD
authors.lastname: Soysal
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: E C
authors.initials: EC
authors.lastname: Obermann
authors.forename: D
authors.initials: D
authors.lastname: Oertli
authors.forename: W E
authors.initials: WE
authors.lastname: Gillanders
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: D061026:Programmed Cell Death 1 Receptor; D018719:Erb-b2 Receptor Tyrosine Kinases; D011971:Receptors, Immunologic; C482586:BTLA protein, human; C105992:PDCD1 protein, human; C508053:ERBB2 protein, human