title: Chronic Activation of Innate Immunity Correlates With Poor Prognosis in Cancer Patients Treated With Oncolytic Adenovirus.
abstract: Despite many clinical trials conducted with oncolytic viruses, the exact tumor-level mechanisms affecting therapeutic efficacy have not been established. Currently there are no biomarkers available that would predict the clinical outcome to any oncolytic virus. To assess the baseline immunological phenotype and find potential prognostic biomarkers, we monitored mRNA expression levels in 31 tumor biopsy or fluid samples from 27 patients treated with oncolytic adenovirus. Additionally, protein expression was studied from 19 biopsies using immunohistochemical staining. We found highly significant changes in several signaling pathways and genes associated with immune responses, such as B-cell receptor signaling (P < 0.001), granulocyte macrophage colony-stimulating factor (GM-CSF) signaling (P < 0.001), and leukocyte extravasation signaling (P < 0.001), in patients surviving a shorter time than their controls. In immunohistochemical analysis, markers CD4 and CD163 were significantly elevated (P = 0.020 and P = 0.016 respectively), in patients with shorter than expected survival. Interestingly, T-cell exhaustion marker TIM-3 was also found to be significantly upregulated (P = 0.006) in patients with poor prognosis. Collectively, these data suggest that activation of several functions of the innate immunity before treatment is associated with inferior survival in patients treated with oncolytic adenovirus. Conversely, lack of chronic innate inflammation at baseline may predict improved treatment outcome, as suggested by good overall prognosis.
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Kristian
authors: K
authors: Taipale
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Ilkka
authors: I
authors: Liikanen
authors: Oncos Therapeutics, Ltd., Helsinki, Finland.
authors: Juuso
authors: J
authors: Juhila
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: Riku
authors: R
authors: Turkki
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Siri
authors: S
authors: Tähtinen
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: Matti
authors: M
authors: Kankainen
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Lotta
authors: L
authors: Vassilev
authors: Department of Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors: Ari
authors: A
authors: Ristimäki
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Anniina
authors: A
authors: Koski
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.|Department of Obstetrics and Gynecology, Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors: Anna
authors: A
authors: Kanerva
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Iulia
authors: I
authors: Diaconu
authors: Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
authors: Vincenzo
authors: V
authors: Cerullo
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Markus
authors: M
authors: Vähä-Koskela
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.
authors: Minna
authors: M
authors: Oksanen
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: Nina
authors: N
authors: Linder
authors: Docrates Cancer Center, Helsinki, Finland.
authors: Timo
authors: T
authors: Joensuu
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: Johan
authors: J
authors: Lundin
authors: University of Helsinki, Faculty of Medicine, Department of Pathology, Cancer Gene Therapy Group, Helsinki, Finland.|Docrates Cancer Center, Helsinki, Finland.|Department of Oncology, HUCH, Helsinki, Finland.|TILT Biotherapeutics Ltd., Helsinki, Finland.
authors: Akseli
authors: A
authors: Hemminki
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000378:metabolism; D016896:Treatment Outcome; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D015704:CD4 Antigens; D011956:Receptors, Cell Surface