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The Role of the JAK/STAT Signalling Pathway in Immunoregulation of Gastrointestinal Cancers

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Immunotherapy for Gastrointestinal Cancer

Abstract

Targeting the immune system as a major therapeutic modality for the treatment of cancer has finally come of age, with immune checkpoint inhibitors leading the way. Better understanding host-tumour interactions will continue to improve our ability to reverse the immune manipulation through which the tumour empowers the immune system to effectively control tumour growth and metastasis. Cytokine signalling mechanisms, such as the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, should be further explored to identify additional points of intervention to aid other immune-targeted approaches. Cytokines and growth factors that utilise the JAK-STAT pathway, including interleukin (IL)-6, IL-12/23, and GM-CSF, play a central role as key messengers between tumour cells and host immune and nonimmune cells in the tumour microenvironment. These cytokines also drive the expression of chemokines that facilitate the influx of immune cells into the tumours. In addition to the immune regulatory function, several components of JAK-STAT signalling, including STAT3 and JAK1, are known to play a direct role in gastrointestinal (GI) cancer oncogenesis, further emphasising the importance of investigating JAK-STAT modulators for the treatment of cancer.

JAK kinases have been studied for well over 20 years as targets for small-molecule drug discovery. Highly selective inhibitors of individual members of the JAK family have been developed and studied in numerous clinical trials. Two JAK inhibitors, the selective JAK1 and JAK2 inhibitor ruxolitinib for the treatment of myelofibrosis and polycythemia vera and the pan-JAK inhibitor tofacitinib for the treatment of rheumatoid arthritis, have been approved by the US Food and Drug Administration and other regulatory agencies around the world. Both agents offer attractive risk-benefit profiles that allowed for their development and subsequent approvals. A substantial body of literature that described preclinical studies of these and other agents supports the hypothesis that targeting the JAK-STAT signalling pathway could be useful for the treatment of GI cancers. Rationally designed clinical trials of JAK-STAT modulators combined with mechanistically supported partners in the appropriate patient population will allow us to evaluate the potential utility of targeting this pathway in the GI cancer setting.

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Kris Vaddi is a consultant to Incyte Corporation.

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  1. Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, DE, 19803, USA

    Kris Vaddi DVM, PhD

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  1. Kris Vaddi DVM, PhD
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  1. Nuffield Division of Clinical and Laboratory Sciences, University of Oxford, Oxford, United Kingdom

    David Kerr

  2. John Radcliffe Hospital, Oxford University Hospitals NHS Trust John Radcliffe Hospital, Oxfordshire, United Kingdom

    Rebecca Johnson

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Vaddi, K. (2017). The Role of the JAK/STAT Signalling Pathway in Immunoregulation of Gastrointestinal Cancers. In: Kerr, D., Johnson, R. (eds) Immunotherapy for Gastrointestinal Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-43063-8_7

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  • DOI: https://doi.org/10.1007/978-3-319-43063-8_7

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