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Interleukins in cancer: from biology to therapy

Nature Reviews Cancer volume 21, pages 481–499 (2021)Cite this article

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Abstract

Interleukins and associated cytokines serve as the means of communication for innate and adaptive immune cells as well as non-immune cells and tissues. Thus, interleukins have a critical role in cancer development, progression and control. Interleukins can nurture an environment enabling and favouring cancer growth while simultaneously being essential for a productive tumour-directed immune response. These properties of interleukins can be exploited to improve immunotherapies to promote effectiveness as well as to limit side effects. This Review aims to unravel some of these complex interactions.

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Fig. 1: Interleukins in carcinogenesis.
Fig. 2: Tumour microenvironment.
Fig. 3: Interleukin-based cancer control.
Fig. 4: Mechanisms of interleukin therapy.

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Acknowledgements

This study was supported by the Marie Skłodowska-Curie Programme Training Network for the Immunotherapy of Cancer and Training Network for Optimizing Adoptive T Cell Therapy of Cancer funded by the Horizon 2020 programme of the European Union (grant 641549 to S.E. and S.K. and grant 955575 to S.K), the Hector Foundation, the international doctoral programme i Target: Immunotargeting of Cancer funded by the Elite Network of Bavaria (S.K. and S.E.), Melanoma Research Alliance grant 409510 (to S.K.), the Else Kröner-Fresenius-Stiftung (S.K.), the German Cancer Aid (S.K.), the Ernst-Jung-Stiftung (S.K.), LMU Munich’s institutional strategy LMUexcellent within the framework of the German Excellence Initiative (S.E. and S.K.), the Bundesministerium für Bildung und Forschung project Oncoattract (S.E. and S.K.), European Research Council grant 756017, ARMOR-T (to S.K.), the German Research Foundation (S.K.), the Fritz Bender Foundation (S.K.), the Bavarian Ministry of Economical Affairs (m4 award to S.K. and S.E.) and the José Carreras Foundation (to S.K.). The authors apologize to any colleagues whose important work could not be cited or commented on due to space restrictions.

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Author notes

  1. These authors contributed equally: Daria Briukhovetska, Janina Dörr.

Authors and Affiliations

  1. Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, LMU, Munich, Germany

    Daria Briukhovetska, Janina Dörr, Stefan Endres & Sebastian Kobold

  2. German Center for Translational Cancer Research (DKTK), Munich, Germany

    Stefan Endres & Sebastian Kobold

  3. Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany

    Stefan Endres & Sebastian Kobold

  4. Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Peter Libby

  5. Department of Medicine, University of Colorado Denver, Aurora, CO, USA

    Charles A. Dinarello

Authors
  1. Daria Briukhovetska
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  2. Janina Dörr
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  4. Peter Libby
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Contributions

S.K., D.B. and J.D. contributed equally to all aspects of the article. S.E., P.L. and C.A.D. contributed to researching literature for the article and discussion of the content, and reviewed or edited the manuscript before submission.

Corresponding author

Correspondence to Sebastian Kobold.

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Competing interests

J.D. has received remuneration from Novartis for work unrelated to this Review. P.L. is an unpaid consultant to, or involved in clinical trials for, Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer and Sanofi-Regeneron. P.L. is a member of scientific advisory board for Amgen, Caristo, Cartesian, Corvidia Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec and XBiotech, Inc. P.L.’s laboratory has received research funding in the past 2 years from Novartis. P.L. is on the Board of Directors of XBiotech, and has a financial interest in Xbiotech, a company developing therapeutic human antibodies. P.L.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. S.K. and S.E. are inventors named on several patents in the field of immuno-oncology unrelated to the present work. S.K. and S.E. received research support from TCR2 Inc. and Arcus Bioscience for work unrelated to this Review. S.K. and S.E. have licensed intellectual property to TCR2 Inc. S.K. has received honoraria from GlaxoSmithKline and Novartis. D.B. and C.A.D. declare no competing interests.

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Nature Reviews Cancer thanks L. Apetoh, who co-reviewed with F. Vegran; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Danger-associated molecular patterns

(DAMPs). Danger-associated molecular patterns and alarmins are endogenous, constitutively expressed, chemotactic and immune-activating proteins and peptides that are released upon degranulation, cell injury or death or in response to immune induction.

Pathogen-associated molecular patterns

(PAMPs). Exogenous conserved microbial structures recognized by the innate immune receptors.

Tumour-associated macrophages

Macrophage subtype that is highly abundant in tumours and associated with immunosuppression, tumour progression and metastasis.

γδ T cells

A subset of T cells differing from conventional T cells by expressing a distinct γδ T cell receptor in contrast to the usual αβ T cell receptor. They do not depend on histocompatibility complex presentation and possess properties of both innate and adaptive immunity

Group 3 innate lymphoid cells

(ILC3s). Cells with characteristics of lymphoid cells but without rearranged antigen-specific surface receptors that are crucial for maintaining homeostasis in the gut microbiota.

Regulatory T cell

(Treg cell). A subtype of T cells maintaining self-tolerance and preventing excessive immune responses, mainly by the inhibition of proliferation and activation of cytotoxic T cells.

Adoptive cell transfer

(ACT). Treatment of patients with ex vivo expanded or modified immune cells usually derived from the patient.

Natural killer (NK) cells

Cytotoxic lymphocytes that can eliminate virus-infected cells or tumour cells by the recognition of non-self antigens presented on major histocompatibility complex class I molecules of the target cell.

Natural killer T cells

(NKT cells). A subset of T cells exhibiting antigen-specific immunity via a restricted T cell receptor recognizing CD1-presented lipid antigens, but also sharing natural killer cell functions in terms of their independence from major histocompatibility complex.

Antigen-presenting cells

(APCs). Dendritic cells, macrophages and B cells that present non-self peptide antigens to T cells via major histocompatibility complex class II molecules.

M1 macrophage

A macrophage subtype associated with inflammation that is characterized by the secretion of the proinflammatory cytokines IL-1, IL-6 and TNF.

Immunotherapy

Treatment of patients with factors shaping an immune response to enable the patient’s immune system to react to the disease.

TH1-type responses

Proinflammatory responses inducing killing of intracellular pathogens and tumour cells mediated mainly by interferon-γ.

M2 macrophages

An inhibitory macrophage subtype associated with tissue remodelling and repair that secrete anti-inflammatory cytokines such as IL-10 and transforming growth factor-β (TGFβ).

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous group of myeloid cells often recruited by tumour cells that lead to pronounced immunosuppression by inhibiting a wide range of inflammatory immune cells.

Group 2 innate lymphoid cells

(ILC2). Cells with characteristics of lymphoid cells but without rearranged antigen-specific surface receptors. Similarly to CD4+ T cells, they produce type 2 cytokines and are also referred to as natural or innate helper cells.

TH2-type responses

Immune responses against mainly extracellular antigens mediated by IL-4, IL-5 and IL-13.

Immune checkpoint inhibitors

(ICIs). Drugs used for therapeutic neutralization of signalling pathways that activate immune checkpoints, which normally lead to the inhibition of immune cell function to keep immune responses under control.

Tumour-infiltrating lymphocytes

Lymphocytes that migrated into the tumour and can be isolated, expanded and re-infused into the patient as therapy.

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Briukhovetska, D., Dörr, J., Endres, S. et al. Interleukins in cancer: from biology to therapy. Nat Rev Cancer 21, 481–499 (2021). https://doi.org/10.1038/s41568-021-00363-z

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