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Therapeutic targeting of tumour myeloid cells

Nature Reviews Cancer volume 23, pages 216–237 (2023)Cite this article

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Abstract

Myeloid cells are pivotal within the immunosuppressive tumour microenvironment. The accumulation of tumour-modified myeloid cells derived from monocytes or neutrophils — termed ‘myeloid-derived suppressor cells’ — and tumour-associated macrophages is associated with poor outcome and resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Unfortunately, there has been little success in large-scale clinical trials of myeloid cell modulators, and only a few distinct strategies have been used to target suppressive myeloid cells clinically so far. Preclinical and translational studies have now elucidated specific functions for different myeloid cell subpopulations within the tumour microenvironment, revealing context-specific roles of different myeloid cell populations in disease progression and influencing response to therapy. To improve the success of myeloid cell-targeted therapies, it will be important to target tumour types and patient subsets in which myeloid cells represent the dominant driver of therapy resistance, as well as to determine the most efficacious treatment regimens and combination partners. This Review discusses what we can learn from work with the first generation of myeloid modulators and highlights recent developments in modelling context-specific roles for different myeloid cell subtypes, which can ultimately inform how to drive more successful clinical trials.

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Fig. 1: Points of potential therapeutic intervention to modify tumour myeloid cells.
Fig. 2: Influence of selected myeloid cell targeted therapies on myeloid cells and the TME.
Fig. 3: Selected therapeutic strategies to reprogramme or stimulate antitumour macrophage function.
Fig. 4: Myeloid cell-mediated therapy resistance in the context of the broader tumour immune landscape.

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Acknowledgements

The authors thank J. Murray for technical assistance and J. Blando for providing the immunohistochemistry images shown in Fig. 4.

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Authors and Affiliations

  1. Bioscience, Early Oncology, AstraZeneca, Cambridge, UK

    Simon T. Barry

  2. Bioscience, Early Oncology, AstraZeneca, Gaithersburg, MD, USA

    Dmitry I. Gabrilovich

  3. Cancer Research UK Beatson Institute, Glasgow, UK

    Owen J. Sansom, Andrew D. Campbell & Jennifer P. Morton

  4. School of Cancer Sciences, University of Glasgow, Glasgow, UK

    Owen J. Sansom & Jennifer P. Morton

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  1. Simon T. Barry
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Corresponding author

Correspondence to Simon T. Barry.

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Competing interests

S.T.B. and D.I.G. are AstraZeneca employees and shareholders. O.J.S. has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis and Cancer Research Horizons. J.P.M. has received research funding from AstraZeneca and UCB Pharma. A.D.C. declares no competing interests.

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Glossary

Chromosome band 9p21

A region of chromosome 9 that in humans encodes the genes CDKN2A, CDKN2B and MTAP and the genes encoding interferon-α and interferon-β. Deletions or mutations of this region occur in many diseases.

Hepatic Kupffer cells

Specialist macrophages in the liver that break down red blood cells as one of their major functions.

Human leukocyte antigen

Part of the major histocompatibility complex antigen presentation complex in humans that is required to present antigens to T cells.

Neutropenia

A reduction in the number of neutrophils in the peripheral blood, common following chemotherapy. Severe reductions in the number of peripheral neutrophils render patients susceptible to infection or febrile neutropenia and is an adverse toxicity.

Phosphatase and tensin homologue

(PTEN). A lipid phosphatase and tumour suppressor that regulates phosphoinositide 3-kinase (PI3K)–AKT pathway activation. PTEN is genetically mutated, deleted or shows reduced expression in many tumour types.

Prostaglandins

Bioactive lipids produced from arachidonic acid that activate multiple G protein-coupled receptors and are produced during inflammation, tissue damage and in the tumour microenvironment, affecting multiple cell types.

STING

A critical effector of the DNA sensing pathway that triggers inflammation-associated responses upon DNA damage.

STK11

The gene encoding the tumour suppressor LKB1, controlling AMPK activation; expression is lost in many tumour types, including lung cancer, rendering tumours refractory to many current treatments associated with accumulation of myeloid cells.

Tenosynovial giant cell tumours

Rare benign tumours driven by overexpression of colony-stimulating factor 1 (CSF1), where CSF1 receptor (CSF1R)-expressing cells such as macrophages accumulate in the tendon sheath and tissue surrounding joints.

β2-Microglobulin

Part of the antigen presentation machinery.

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Barry, S.T., Gabrilovich, D.I., Sansom, O.J. et al. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer 23, 216–237 (2023). https://doi.org/10.1038/s41568-022-00546-2

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