title: Prognostic Implications of Tumor-Infiltrating Lymphocytes in Association With Programmed Death Ligand 1 Expression in Early-Stage Breast Cancer.
abstract: BACKGROUND
  The immune system might influence breast cancer (BC) prognosis. However, the relationship between programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocyte (TIL) profiles remains unclear with respect to BC subtypes.
  
  
  METHODS
  We investigated the relationship between TIL profiles for CD8+ and forkhead box P3-positive (FOXP3+) and PD-L1 expression in primary tumor tissue using immunohistochemistry and the clinical outcomes in 2 patient cohorts at the National Cancer Center: 256 patients diagnosed with early-stage BC from January 2001 to December 2005 and 77 hormone receptor (HR)-negative BC patients diagnosed from January 2006 to December 2008. Clinical data were collected, including HR status, human epidermal growth factor receptor 2 expression, disease-free survival, and overall survival (OS).
  
  
  RESULTS
  The median patient age was 47 years (range, 28-78), and the median follow-up period was 9.8 years. Of the 333 patients, 186 (55.9%) had HR-positive and 125 (37.5%) had node-positive BC. We found a strong positive correlation between CD8+ TILs and FOXP3+ TILs (P < .001). CD8+ TILs were more abundant in tumors with low PD-L1 expression (P < .001), although no association was found between FOXP3+ TILs and PD-L1 expression. More CD8+ TILs were present in HR-negative than in HR-positive BC (P < .001), and PD-L1 expression was more frequent in HR-positive BC (P < .001). A greater number of CD8+ TILs (increase in quartile) was strongly associated with OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.95; P = .03) only in HR-negative BC when adjusted for various clinical factors. PD-L1 expression and FOXP3+ TILs did not exhibit such associations.
  
  
  CONCLUSIONS
  Higher CD8+ lymphocyte infiltration was related to lower PD-L1 expression and higher FOXP3+ TIL infiltration in BC. Higher CD8+ TIL expression was associated with prolonged survival only in those with HR-negative BC.
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea; Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: In Hae
authors.initials: IH
authors.lastname: Park
authors.affiliation: Translational Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research Institute, National Cancer Center, Goyang-si, Korea; Department of Laboratory Medicine, Center for Diagnostic Oncology, Hospital and Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.affiliation: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, Houston, TX.
authors.forename: Jae Yoon
authors.initials: JY
authors.lastname: Ro
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea; Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: Youngmee
authors.initials: Y
authors.lastname: Kwon
authors.affiliation: Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Mo
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea; Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Jung
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea.
authors.forename: Seeyoun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea.
authors.forename: Keun Seok
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea; Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Kang
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea; Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea.
authors.forename: Eunsook
authors.initials: E
authors.lastname: Lee
authors.affiliation: Biometric Research Branch, National Cancer Center, Goyang-si, Korea.
authors.forename: Jungnam
authors.initials: J
authors.lastname: Joo
authors.affiliation: Center for Breast Cancer, National Cancer Center, Goyang-si, Korea; Breast and Endocrine Center Branch of Research Institute, National Cancer Center, Goyang-si, Korea. Electronic address: jungsro@ncc.re.kr.
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
mesh_terms: D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human
keywords: Hormone receptor; Immunohistochemistry; PD-L1; Prognosis; Tumor infiltrating lymphocytes