title: Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma.
abstract: Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumor-associated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P=0.0004, and telomerase with and without macrophages P=0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs >76% for all other subtypes, P=0.014). In summary, different immune signatures are found among telomere maintenance mechanism-based subgroups in glioblastoma. The reduced extent of surgical resection of telomerase-positive tumors with macrophages suggests that some tumor-associated macrophages are more unfavorable.
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Noelyn A
authors.initials: NA
authors.lastname: Hung
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Ramona A
authors.initials: RA
authors.lastname: Eiholzer
authors.affiliation: Department of Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Stenar
authors.initials: S
authors.lastname: Kirs
authors.affiliation: Department of Radiology, Southern District Health Board, Dunedin, New Zealand.
authors.forename: Jean
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology and Immunology, Dunedin School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Ward-Hartstonge
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Wiles
authors.affiliation: Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Frampton
authors.affiliation: Neurosurgery, Southern District Health Board, Dunedin, New Zealand.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Taha
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Royds
authors.affiliation: Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
authors.forename: Tania L
authors.initials: TL
authors.lastname: Slatter
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016615:Telomere / Q000502:physiology*