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Macrophages as regulators of tumour immunity and immunotherapy

Abstract

Macrophages are critical mediators of tissue homeostasis, with tumours distorting this proclivity to stimulate proliferation, angiogenesis and metastasis. This had led to an interest in targeting macrophages in cancer, and preclinical studies have demonstrated efficacy across therapeutic modalities and tumour types. Much of the observed efficacy can be traced to the suppressive capacity of macrophages, driven by microenvironmental cues such as hypoxia and fibrosis. As a result, tumour macrophages display an ability to suppress T cell recruitment and function as well as to regulate other aspects of tumour immunity. With the increasing impact of cancer immunotherapy, macrophage targeting is now being evaluated in this context. Here, we discuss the results of clinical trials and the future of combinatorial immunotherapy.

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Fig. 1: Macrophage origin and polarization state.
Fig. 2: Direct and indirect regulation of tumour immunity by TAMs.
Fig. 3: Cell type versus integrated views on drivers of TAM phenotype.

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Acknowledgements

The laboratory of D.G.D. is supported by funding from the National Cancer Institute, including P50CA196510, R01CA177670, R01CA203890 and P30CA091842 Supplement-15S3, as well as The Mary Kay Foundation. The laboratory of B.R. is supported by funding from the National Institutes of Health (R00CA185325), the Florida Department of Health Bankhead-Coley Cancer Research Program (8BC02) and the Florida Breast Cancer Foundation. The authors thank members of their laboratories for helpful discussion.

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Nature Reviews Immunology thanks M. De Palma, J. Guerriero and S. Patel for their contribution to the peer review of this work.

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Correspondence to David G. DeNardo or Brian Ruffell.

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Glossary

Tumour microenvironment

(TME). The cellular and acellular components in which malignant cells reside. These include surrounding blood vessels, immune cells, fibroblasts, extracellular matrix components and extracellular signalling molecules such as chemokines, cytokines and growth factors, as well as metabolic regulators such as oxygen.

Tumour immune microenvironment

(TIME). The components of the tumour microenvironment represented by leukocytes or their derived factors.

M1–M2 macrophage polarization

M1 and M2 are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when classically activated with IFNγ and lipopolysaccharide) or anti-inflammatory (when alternatively activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regards to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Desmoplasia

When associated with cancer, the growth and expansion of fibrous and/or connective tissue surrounding the malignant cells. Desmoplasia may occur around a growing neoplasm and consists of expansion of the non-malignant cellular components, such as activated fibroblasts, beyond the norms of the homeostatic tissue levels.

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DeNardo, D.G., Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol 19, 369–382 (2019). https://doi.org/10.1038/s41577-019-0127-6

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