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Tumour-associated macrophages as treatment targets in oncology

Nature Reviews Clinical Oncology volume 14, pages 399–416 (2017)Cite this article

Subjects

Key Points

  • Tumour-associated macrophages (TAMs) are a key component of the cancer microenvironment, and influence tumour growth and progression

  • TAMs can have a dual supportive and inhibitory influence on cancer, depending on the disease stage, the tissue involved, and the host microbiota

  • TAMs can limit the antitumour activity of conventional chemotherapy and radiotherapy by orchestrating a tumour-promoting repair response to tissue damage, and by providing a protective niche for cancer stem cells

  • Conversely, TAMs contribute to the antitumour activity of selected chemotherapeutic agents, such as doxorubicin (under certain conditions), and of monoclonal antibody therapies via antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP)

  • Of note, macrophage depletion has a key role in the antitumour activity of the clinically approved anticancer agent trabectedin

  • Therapeutic strategies targeting macrophages as tumour-promoting factors, and/or aimed at macrophage activation and re-education are undergoing clinical assessment; such strategies have the potential to complement cytoreductive, antiangiogenic, and immune-checkpoint-inhibitor treatments

Abstract

Macrophages are crucial drivers of tumour-promoting inflammation. Tumour-associated macrophages (TAMs) contribute to tumour progression at different levels: by promoting genetic instability, nurturing cancer stem cells, supporting metastasis, and taming protective adaptive immunity. TAMs can exert a dual, yin–yang influence on the effectiveness of cytoreductive therapies (chemotherapy and radiotherapy), either antagonizing the antitumour activity of these treatments by orchestrating a tumour-promoting, tissue-repair response or, instead, enhancing the overall antineoplastic effect. TAMs express molecular triggers of checkpoint proteins that regulate T-cell activation, and are targets of certain checkpoint-blockade immunotherapies. Other macrophage-centred approaches to anticancer therapy are under investigation, and include: inhibition of macrophage recruitment to, and/or survival in, tumours; functional re-education of TAMs to an antitumour, 'M1-like' mode; and tumour-targeting monoclonal antibodies that elicit macrophage-mediated extracellular killing, or phagocytosis and intracellular destruction of cancer cells. The evidence supporting these strategies is reviewed herein. We surmise that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapy.

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Figure 1: A schematic representation of the role of tumour-associated macrophages (TAMs) in tumour progression.
Figure 2: Mechanisms of tumour-associated macrophage (TAM)-mediated immune suppression.
Figure 3: The yin and yang of tumour-associated macrophages (TAMs) in response to chemotherapy and radiotherapy.
Figure 4: Macrophage-targeting antitumour treatment approaches.

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Acknowledgements

The work of the authors is supported by the Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research; A. Mantovani, F.M., L.L., and P.A.), the European Research Council (ERC Advanced Grant to A. Mantovani), the Fondazione Cariplo (Cariplo Foundation; A. Mantovani), the Italian Ministry of Health (A. Mantovani), and Worldwide Cancer Research, UK (P.A.). The authors thank Dr Hridayesh Prakash for stimulating discussions on clodronate and visceral metastasis.

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Authors and Affiliations

  1. Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Via A. Manzoni 113, Rozzano, Milan, 20089, Italy

    Alberto Mantovani, Federica Marchesi, Alberto Malesci, Luigi Laghi & Paola Allavena

  2. Humanitas University, Via A. Manzoni 113, Rozzano, Milan, 20089, Italy

    Alberto Mantovani & Paola Allavena

  3. Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Vanvitelli 32, Milan, 20133, Italy

    Federica Marchesi & Alberto Malesci

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  1. Alberto Mantovani
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Contributions

A. Mantovani, F.M. and P.A. contributed equally to this Review. A. Mantovani, F.M., and P.A researched the data for the article. A. Mantovani, F.M., L.L, and P.A. wrote the manuscript. A. Malesci contributed to discussion of content. All authors reviewed and/or edited of the manuscript before submission.

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Correspondence to Alberto Mantovani.

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Mantovani, A., Marchesi, F., Malesci, A. et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14, 399–416 (2017). https://doi.org/10.1038/nrclinonc.2016.217

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