title: Therapeutic implications of CD1d expression and tumor-infiltrating macrophages in pediatric medulloblastomas.
abstract: Immunobiology of medulloblastoma (MB), the most common malignant brain tumor in children, is poorly understood. Although tumor cells in some MBs were recently shown to express CD1d and be susceptible to Vα24-invariant natural killer T (NKT)-cell cytotoxicity, the clinical relevance of CD1d expression in MB patients remains unknown. We investigated the expression of CD1d in pediatric MBs and correlated with molecular and clinical characteristics. Specifically, we explored if NKT cell therapy can be targeted at a subset of pediatric MBs with poorer prognosis. Particularly, infantile MBs have a worse outcome because radiotherapy is delayed to avoid neurocognitive sequelae. Immunohistochemistry for CD1d was performed on a screening set of 38 primary pediatric MBs. Gene expression of the membrane form of M2 macrophage marker, CD163, was studied in an expanded cohort of 60 tumors. Outcome data was collected prospectively. Thirteen of 38 MBs (34.2 %) expressed CD1d on immunohistochemistry. CD1d was expressed mainly on MB tumor cells, and on some tumor-associated macrophages. Majority (18/22, 82 %) of non sonic-hedgehog/Wingless-activated MBs (group 3 and 4) were CD1d-negative (p = 0.05). A subset of infantile MBs (4/9, 44.4 %) expressed CD1d. Macrophages infiltrating MB expressed CD163 apart from CD1d. Molecular subtypes demonstrated statistical differences in CD163 expression, SHH-tumors were the most enriched (p = 0.006). Molecular and clinical subtypes of pediatric MB exhibit distinct differences in CD1d expression, which have important therapeutic implications. High CD1d expression in infantile MBs offers potential new immunotherapeutic treatment with NKT cell therapy in infants, where treatment is suboptimal due delayed radiotherapy.
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, 1102 Bates street, 1030.11, Feigin Center, Houston, TX, 77030, USA, wywlzl@singnet.com.sg.
authors.forename: Wan-Yee
authors.initials: WY
authors.lastname: Teo
authors.forename: M Tarek
authors.initials: MT
authors.lastname: Elghetany
authors.forename: Jianhe
authors.initials: J
authors.lastname: Shen
authors.forename: Tsz-Kwong
authors.initials: TK
authors.lastname: Man
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Li
authors.forename: Murali
authors.initials: M
authors.lastname: Chintagumpala
authors.forename: Jack Meng Fen
authors.initials: JM
authors.lastname: Su
authors.forename: Robert
authors.initials: R
authors.lastname: Dauser
authors.forename: William
authors.initials: W
authors.lastname: Whitehead
authors.forename: Adekunle M
authors.initials: AM
authors.lastname: Adesina
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000378:metabolism / Q000473:pathology*; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D055610:Antigens, CD1d; D014408:Biomarkers, Tumor; C526877:CD1D protein, human; D012333:RNA, Messenger