Abstract
Bladder cancer is an important public health concern owing to its prevalence, high recurrence risk and treatment failures. Maintaining the equilibrium between prompt and effective immunity and an excessive and protracted immune response is critical for successful immune defence. This delicate balance is ensured by intrinsic or extrinsic immunoregulatory mechanisms. Intrinsic control of immune cell activation is mediated by stimulatory and inhibitory receptors expressed on the effector cell itself, whereas extrinsic control is mediated via other immune cells by cell–cell contact and/or secretion of inhibitory factors. Tumours can exacerbate these immunosuppressive pathways, fostering a tolerant microenvironment. These mechanisms have previously been poorly described in urothelial carcinoma, but a growing body of evidence highlights the key role of immune regulation in bladder cancer. This process includes immune checkpoints (mostly programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)), as well as regulatory T cells, myeloid-derived suppressor cells, tumour-associated macrophages and type 2 innate and adaptive lymphocytes. For each component, quantitative and qualitative alterations, clinical relevance and potential targeting strategies are currently being explored. An improved understanding of immune regulation pathways in bladder cancer development, recurrence and progression will help in the design of novel diagnostic and prognostic tools as well as treatments.
Key points
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Immune regulatory mechanisms can be divided into intrinsic and extrinsic pathways, which include inhibitory and stimulatory receptors and regulatory cells, respectively.
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The programmed cell death 1 (PD-1)–programmed cell death 1 ligand 1 (PD-L1) pathway is involved in bladder cancer immune regulation, and PD-L1 blockade results in impressive outcomes in patients with advanced disease; ongoing clinical trials are testing the effect of combined bacillus Calmette–Guérin (BCG) and anti-PD-L1 treatment.
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The utility of inhibitory receptors (mostly PD-L1) as prognostic markers has proven difficult owing to conflicting results, highlighting the need to define standardized measurement methods.
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Regulatory T cells and myeloid-derived suppressor cells (MDSCs) are key regulators of anti-tumour responses in bladder cancer, and type 2 immunity (TH2 cells and ILC2s) seems to also have an important function, especially in BCG therapy.
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Future investigation of regulatory pathways involved in bladder tumour development and/or treatment failure will hopefully lead to the design of new immunotherapeutic strategies and predictors of clinical outcomes.
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Acknowledgements
Research in the Derré lab is supported by The Swiss Cancer League (# KFS-4101–02–2017).
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Schneider, A.K., Chevalier, M.F. & Derré, L. The multifaceted immune regulation of bladder cancer. Nat Rev Urol 16, 613–630 (2019). https://doi.org/10.1038/s41585-019-0226-y
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DOI: https://doi.org/10.1038/s41585-019-0226-y
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