Abstract Immunotherapies, although promising in pre- clinical studies, have not yet enhanced the survival of pa- tients with glioblastomas. To further understand the im- munobiology of glioblastomas in clinical settings, we ex- amined 53 cytokine or cytokine receptor transcripts in 12 human glioblastomas and 6 human glioblastoma cell lines and correlated the findings with the degree of inflamma- tion. Multi-probe RNase protection assays were used to examine Th1, Th2, and Th3 cytokine and cytokine recep- tor expression. Th2 [interleuking (IL)-6, leukemia in- hibitory factor and oncostatin M] and Th3 (transforming growth factor-β1, 2, 3) cytokine and their receptor tran- scripts were strongly expressed in almost all glioblastomas and glioma cell lines. Two other Th2 cytokine receptor subunit transcripts (IL-4Rα and IL-13Rα) were also com- monly detected. In contrast, although Th1 cytokine recep- tors tumor necrosis factor (TNF) RI, interferon (IFN)-γRα, IFN-γRβ, were detected, their cytokines (IFN-γ, TNF-α, lymphotoxin-α) were not. Transcripts for IL-2 family cy- tokine (IL-2, IL-7, IL-9, IL-15) and receptors (IL-2Rα, IL-2Rβ, γc, IL-7Rα, IL-9Rα, IL15Rα) and IL-12 family cytokine (IL-12p40) and receptors (IL-12Rβ1 and IL-12β2) were essentially absent in both tumors and cell lines. Im- munohistochemical methods showed sparse T lymphocyte infiltrates and numerous microglia in the glioblastomas. This pattern indicates an ‘immunosuppressive status’ in glioblastomas and could account for the failure of im- munotherapy in such tumors. Keywords Cytokine · Receptor · Glioblastoma · Cell lines · Immunotherapy Introduction Malignant astrocytomas (anaplastic astrocytoma, glioblas- toma) are the most common and aggressive of human brain tumors. Despite intensive research, various widely em- ployed treatment regimes for patients with these tumors have not significantly improved the prognosis. Immuno- therapy is a theoretically attractive, alternative method of treatment since tumor cells can be selectively targeted [2]. However, despite encouraging results in the research lab- oratories, neither adoptive immunotherapies [18, 26] nor recently developed active immunogene therapies [7, 35] have yet led to successful tumor eradication. Recent ob- servations suggest the immune system’s failure to recog- nize tumor cells may, in part, be attributed to tumor-asso- ciated cytokine dysregulation [36, 48, 50]. Our understanding of cytokine regulation has been fa- cilitated by the Th1/Th2 model in which different T helper (Th) lymphocyte subsets secrete cytokines whose proper- ties vary with the nature of the immune response gener- ated [29]. Th1 (proinflammatory) cytokines include inter- feron-γ (IFN-γ), interleukin-2 (IL-2), IL-12, IL-15, lym- photoxin (LT), and tumor necrosis factor-α (TNF-α). Since these molecules promote cell-mediated immune re- sponses they have the potential to exert anti-tumor effects. In contrast, Th2 (immunosuppressive) cytokines such as IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 stimulate humoral immune responses and thus down-regulate tumor-specific immunity. Also strongly immunosuppressive are cytokines, referred to as ‘Th3’, which include members of the trans- forming growth factor (TGF)-β family [4]. Glioblastoma cells appear to secrete Th2 (IL-6, IL-10) [13, 20] and Th3 (TGF-β) cytokines [5, 34], whose im- munosuppressive properties may abrogate cytotoxic anti- Chunhai Hao · Ian F. Parney · Wilson H. Roa · Joan Turner · Kenneth C. Petruk · David A. Ramsay Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation Acta Neuropathol (2002) 103 : 171–178 DOI 10.1007/s004010100448 Received: 22 January 2001 / Revised, accepted: 19 July 2001 / Published online: 22 November 2001 REGULAR PAPER C. Hao (✉) Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada T6G 2B7 e-mail: chao@ualberta.ca I.F. Parney · K.C. Petruk Department of Surgery, University of Alberta, Edmonton, Alberta, Canada T6G 2B7 W.H. Roa · J. Turner Department of Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 2B7 D.A. Ramsay Department of Pathology, University of Western Ontario, London, Ontario, Canada N6A 4G5 © Springer-Verlag 2001