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Cytokine networks in glioma

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Abstract

Glioma is the most frequently occurring brain tumor, but the prognosis of patients with gliomas remains poor despite advances in surgery, radiotherapy, and chemotherapy. Therefore, great efforts have been made to develop improved therapeutic strategies. Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins that exert pleiotropic and redundant effects that promote the growth, differentiation, and activation of normal cells. Cytokines have either pro- or anti-inflammatory activity and immunosuppressive activity, depending on the microenvironment surrounding the tumor. The microenvironment consists of heterogeneous tumor cells, immune cells, and extracellular matrix. Modulation of the microenvironment by the tumor is essential for its growth and progress. Cytokine production acts as a means of communication in the tumor microenvironment. In this article, we review the cross-talk between cytokines in the tumor microenvironment and the cytokine therapies that have been used till date for glioma treatment.

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Authors and Affiliations

  1. Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Kenichiro Iwami, Atsushi Natsume & Toshihiko Wakabayashi

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  1. Kenichiro Iwami
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  2. Atsushi Natsume
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  3. Toshihiko Wakabayashi
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Correspondence to Toshihiko Wakabayashi.

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Karl Frei, Zurich, Switzerland

In this review, the authors discuss aspects of cytokine networks in gliomas and attempt to provide some explanations for the poor successes of clinical trials using cytokine-based drugs or cytokine gene therapy.

The cross-talk between glioma cells and their immunological microenvironment leading to tumor-induced immunosuppression is addressed and the numerous factors involved discussed. Although the immunosuppressive effect of glioblastoma has long been recognized, the molecular basis for the cross-talk between tumor and immune cells remains still largely unknown. What is the underlying mechanism that allows a tumor to produce immunsuppressive factors that generate tolerogenic dendritic cells and regulatory T cells in the glioma microenvironment? Why are the innate immune cells (macrophages, natural killer cells, and neutrophils) incapable of killing glioma cells?

The definition of specific molecules and signalling pathways (e.g., signal transducer and activator of transcription 3, STAT3) that regulate the tumor microenvironment will provide important targets for cancer immunotherapy in the future.

Michael Weller, Zurich, Switzerland

Glioblastoma has been recognized as a paradigmatic neoplasm for the interaction of cancer cells with the host’s immune system for decades. These tumors produce several cytokines not classically associated with astrocytic cells, including interleukins as well as immunosuppressive, proinvasive, and angiogenic cytokines. This vast repertoire of soluble mediators allows for complex autocrine and paracrine interactions as well as a profound impact on the cells of the glioblastoma microenvironment. In this regard, it is important to note that, although glioblastomas do not possess a typical stroma like many neoplasms outside the nervous system, glioblastomas are still heavily infiltrated by non-neoplastic cells, including macrophages and microglial cells, reactive astrocytes, and immune cells from the periphery. The most important cytokines as of today appear to be (i) transforming growth factor-β which is at once strongly immunosuppressive, promigratory and proinvasive, and (ii) vascular endothelial growth factor which is considered the driving force of angiogenesis in these tumors. Future studies will have to clarify for each of these soluble factors the cellular source, the major cellular target, and the overall contribution to tumor progression versus tumor defense mechanisms. A deeper understanding of such interactions is required to fully exploit the potential of cytokines and cytokine-targeted therapeutic approaches to glioblastoma.

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Iwami, K., Natsume, A. & Wakabayashi, T. Cytokine networks in glioma. Neurosurg Rev 34, 253–264 (2011). https://doi.org/10.1007/s10143-011-0320-y

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  • DOI: https://doi.org/10.1007/s10143-011-0320-y

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