title: HHLA2, a New Immune Checkpoint Member of the B7 Family, Is Widely Expressed in Human Lung Cancer and Associated with EGFR Mutational Status.
abstract: OBJECTIVE
  Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC.
  
  
  METHODS
  We performed IHC with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinicopathologic characteristics of these patients.
  
  
  RESULTS
  Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR-mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P = 0.01) and validation cohorts (89% vs. 69%, P = 0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared with squamous and large cell histology, non-Hispanic White versus Hispanics, and tumors with high tumor-infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.
  
  
  CONCLUSIONS
  HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy. Clin Cancer Res; 23(3); 825-32. ©2016 AACR.
authors.affiliation: Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York. hcheng@montefiore.org xing-xing.zang@einstein.yu.edu.
authors.forename: Haiying
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Murali
authors.initials: M
authors.lastname: Janakiram
authors.affiliation: Department of Pathology, Weill Cornell Medicine, New York, New York.
authors.forename: Alain
authors.initials: A
authors.lastname: Borczuk
authors.affiliation: Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.affiliation: Irving Cancer Research Center, Columbia University Medical Center, New York, New York.
authors.forename: Wanglong
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Huijie
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Chinai
authors.affiliation: Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
authors.affiliation: Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Roman
authors.initials: R
authors.lastname: Perez-Soler
authors.affiliation: Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York. hcheng@montefiore.org xing-xing.zang@einstein.yu.edu.|Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000368:Aged; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis*; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis*; D044469:Racial Groups / Q000235:genetics; D012189:Retrospective Studies; D046888:Tissue Array Analysis
chemical_list: C400341:HHLA2 protein, human; D007136:Immunoglobulins; D009363:Neoplasm Proteins