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Review
. 2021 Mar;18(3):566-578.
doi: 10.1038/s41423-020-00613-4. Epub 2021 Jan 20.

Tumor-associated myeloid cells: diversity and therapeutic targeting

Alberto Mantovani  1   2   3 , Federica Marchesi  4   5 , Sebastien Jaillon  4   6 , Cecilia Garlanda  4   6 , Paola Allavena  4
Affiliations
Review

Tumor-associated myeloid cells: diversity and therapeutic targeting

Alberto Mantovani et al. Cell Mol Immunol. 2021 Mar.

Abstract

Myeloid cells in tumor tissues constitute a dynamic immune population characterized by a non-uniform phenotype and diverse functional activities. Both tumor-associated macrophages (TAMs), which are more abundantly represented, and tumor-associated neutrophils (TANs) are known to sustain tumor cell growth and invasion, support neoangiogenesis and suppress anticancer adaptive immune responses. In recent decades, several therapeutic approaches have been implemented in preclinical cancer models to neutralize the tumor-promoting roles of both TAMs and TANs. Some of the most successful strategies have now reached the clinic and are being investigated in clinical trials. In this review, we provide an overview of the recent literature on the ever-growing complexity of the biology of TAMs and TANs and the development of the most promising approaches to target these populations therapeutically in cancer patients.

Keywords: macrophage targeting; tumor microenvironment; tumor-associated macrophages.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Origins of tumor-associated myeloid cells. Tumor-associated neutrophils (TANs) and macrophages (TAMs) originate from bone marrow monocytic and neutrophilic precursors, respectively, released into the circulation. Chemokines and other chemoattractants (including CCL2, CCL5, and CXCL12) produced by cellular components of the tumor microenvironment induce the recruitment of myeloid cells to tumor tissue. Once in the microenvironment, TAMs and TANs display several protumor functions, such as sustaining tumor-promoting inflammation, stimulating tumor cell proliferation, inducing T cell immunosuppression, organizing tissue remodeling responses, and stimulating angiogenesis, favoring invasion and metastasis
Fig. 2
Fig. 2
Strategies for reprogramming macrophages in cancer. Tumor-educated macrophages have several tumor-promoting functions. Strategies to reprogram TAMs into M1-like antitumor effectors are depicted in the figure. Blockade of SIRP1α molecules with inhibitory antibodies reactivates the phagocytosis of tumor cells. Agonistic antibodies specific for the receptor CD40 or ligands of Toll-like receptors (TLRs) trigger TAM antitumor cytotoxic activity and induce the production of immunostimulatory cytokines and chemokines that recruit and activate T cells as part of an adaptive immune response. The altered metabolism of the tumor environment impacts the functional activity of TAMs; compounds inhibiting specific metabolic factors may relieve the stress caused by altered tumor metabolism and rewire the functional activity of macrophages
Fig. 3
Fig. 3
Strategies for targeting neutrophils in cancer. Inhibition of CXC chemokines or their receptors CXCR1 and CXCR2 can limit the mobilization and recruitment of neutrophils into the tumor microenvironment. Treatment with IFNβ or GM-CSF + IFNγ or blockade of TGFβ, AGTR1, FATP2 or CXCR4 induces the polarization or reprogramming of neutrophils into an activated antitumor state characterized by cytotoxic activity towards cancer cells or activation of an antitumor immune response. Neutrophils express the ligands of the lymphocyte checkpoint molecules PD-1 and VISTA and the myeloid checkpoint molecules LILRB2 and SIRPα, which represent potential targets to inhibit the immunosuppressive activities of neutrophils and improve their effector activities. The expression of FcαRI and FcγRI by neutrophils represents a target for the elimination of antibody-opsonized cancer cells through the processes of antibody-dependent cellular cytotoxicity (ADCC) and trogoptosis
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