title: Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein.
abstract: OBJECTIVE
  HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors.
  
  
  METHODS
  An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors.
  
  
  RESULTS
  HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2.
  
  
  CONCLUSIONS
  Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York. 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 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: Susan
authors.initials: S
authors.lastname: Fineberg
authors.affiliation: Department of System and Computational Biology, Biochemistry, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Andras
authors.initials: A
authors.lastname: Fiser
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Medavarapu
authors.affiliation: Department of Pathology, Yale New Haven Hospital, New Haven, Connecticut.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Castano
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Jeon
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Kim C
authors.initials: KC
authors.lastname: Ohaegbulam
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York. xing-xing.zang@einstein.yu.edu jsparano@montefiore.org.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York. Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York. xing-xing.zang@einstein.yu.edu jsparano@montefiore.org.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D018106:CD28 Antigens / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D005260:Female; D015870:Gene Expression; D006031:Glycosylation; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D008207:Lymphatic Metastasis; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D018106:CD28 Antigens; C400341:HHLA2 protein, human; D007136:Immunoglobulins; C585279:TMIGD2 protein, human