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The role of myeloid cells in cancer therapies
Nature Reviews Cancervolume 16, pages447–462 (2016)Cite this article
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Key Points
Myeloid cells can be abundant in the tumour stroma and emerging evidence indicates that the presence of these cells influences patient outcome in many cancer types.
Myeloid cells comprise various subsets that exhibit divergent functions. Whereas most myeloid cells promote cancer outgrowth, others display potent antitumour activity.
Tumours co-opt myeloid cells to promote cancer growth. This process occurs not only within the local tumour microenvironment but also in various distant body compartments.
Myeloid cells can favour or hinder each step of the metastatic cascade.
Myeloid cells have a central, yet still largely unexplored, role in virtually all therapeutic modalities, including surgery, chemotherapy, radiotherapy, immunotherapy and targeted therapy.
Modulating myeloid cell functions in therapy is an attractive option to augment the efficacy of current treatment options.
Abstract
Recent clinical trials have demonstrated the ability to durably control cancer in some patients by manipulating T lymphocytes. These immunotherapies are revolutionizing cancer treatment but benefit only a minority of patients. It is thus a crucial time for clinicians, cancer scientists and immunologists to determine the next steps in shifting cancer treatment towards better cancer control. This Review describes recent advances in our understanding of tumour-associated myeloid cells. These cells remain less studied than T lymphocytes but have attracted particular attention because their presence in tumours is often linked to altered patient survival. Also, experimental studies indicate that myeloid cells modulate key cancer-associated activities, including immune evasion, and affect virtually all types of cancer therapy. Consequently, targeting myeloid cells could overcome limitations of current treatment options.
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Acknowledgements
The authors thank members of the Pittet laboratory and of the Massachusetts General Hospital (MGH) Center for Systems Biology for critical discussions and acknowledge all contributors to the field whose work we could not cite owing to space limitations. This work was supported in part by the Samana Cay MGH Research Scholar Fund, National Institutes of Health (NIH) grants P50-CA86355, R21 CA190344 and R01-AI084880 (to M.J.P.), the Boehringer Ingelheim Fonds (to C.E.) and the Deutsche Forschungsgemeinschaft (DFG) PF809/1-1 (to C.P.).
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Camilla Engblom and Christina Pfirschke: These authors contributed equally to this work.
Authors and Affiliations
Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, 02114, Massachusetts, USA
Camilla Engblom, Christina Pfirschke & Mikael J. Pittet
Graduate Program in Immunology, Harvard Medical School, Boston, 02115, Massachusetts, USA
Camilla Engblom
- Camilla Engblom
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- Christina Pfirschke
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- Mikael J. Pittet
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Correspondence toMikael J. Pittet.
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Glossary
- Innate immune system
A system comprising various cell types that together provide defence to the host against infection and injury and orchestrate inflammatory responses. Unlike adaptive immune cells, innate immune cells express only germline-encoded pattern recognition receptors and generally they do not provide long-lasting immunity; however, they can activate the adaptive immune system through a process known as antigen presentation.
- Macrophages
Differentiated cells of the mononuclear phagocyte lineage that can clear dead cells and foreign particles through a process called phagocytosis. Macrophages assume tissue- and microenvironment-specific phenotypes to regulate tissue homeostasis, immunity and inflammation; they are essential protectors against injury and infections but also contribute to many diseases, including cancer.
- Dendritic cells
(DCs). Crucial antigen-presenting cells for immune control. DCs typically have a probing morphology and localize in T cell areas of lymphoid organs to activate specific CD4+ and CD8+ T cells, but they can also be found in nonlymphoid tissues, such as the tumour stroma.
- Monocytes
Bone marrow-derived mononuclear phagocytes, crucial in protection against infections and in immune homeostasis, which when deployed to tissues can differentiate into a macrophage, and under certain conditions, a dendritic cell. Monocytes are typically divided into two subtypes: patrolling monocytes and inflammatory monocytes.
- Neutrophils
Polymorphonuclear cells that develop and mature in the bone marrow, exist at high numbers in circulation and can be rapidly recruited to a site of injury or inflammation. Neutrophils can release potent biologically active antimicrobial enzymes, which are directly involved in clearance of infection.
- Eosinophils
Granulocytic cells that are known mostly for their involvement in asthmatic disease and parasitic infections. Eosinophils are found primarily in the circulation, gut and thymic tissue but can be rapidly deployed into various tissues during inflammation to expel their granular content.
- Mast cells
Crucial innate effector cells that are rich in granules that contain various immunoregulatory molecules. Upon stimulation by pathogens, allergens or endogenous factors, mast cells can rapidly degranulate and profoundly affect local and systemic tissue homeostasis, as exemplified by anaphylaxis.
- Basophils
Circulating granulocytic cells known to mediate allergic responses and host defence against parasitic infections. Basophilic granules are a rich source of inflammatory mediators, including the vasodilator histamine and the anticoagulant heparin.
- Tertiary lymphoid structures
Ectopic lymph node-like arrangements that form in tissues under pathophysiological conditions and that seem to facilitate local lymphocyte activation.
- Regulatory T cells
(Treg cells). Specialized T cells that are functionally defined by their ability to confer peripheral tolerance to self, commensal and environmental antigens. Treg cell accumulation in tumours can suppress antitumour immunity and is associated with poor prognosis in many cancers.
- Degranulation
Release of cytotoxic and other molecules from secretory vesicles, also called granules, that are initially stored in some innate immune cells, for example, neutrophils, eosinophils and mast cells.
- M-CSF–M-CSFR
(macrophage-colony stimulating factor and its receptor, also known as CSF1–CSF1R). A haematopoietic growth factor–receptor pair that is required for proper development, survival and maintenance of the monocyte and macrophage cell lineage.
- CCL2–CCR2
(chemokine (C-C motif) ligand/receptor 2). A chemokine–receptor pair that mediates monocyte release from the bone marrow and, in the context of cancer, entry into the tumour microenvironment.
- Premetastatic sites
Sites in which metastasis will occur. These sites are thought to be primed for tumour cell engraftment by factors that are secreted by the primary tumour and by bone marrow-derived haematopoietic cells that are recruited locally.
- Natural killer (NK) cells
Cytotoxic lymphocytes that are crucial to the innate immune system and that provide rapid responses to eliminate abnormal cells, such as virus-infected cells and tumour cells.
- Fcγ-receptor
(FcγR). A surface-bound protein receptor expressed by phagocytes and other cell types, which binds to the constant heavy chain (Fc) region of an antibody and mediates cell clearance mechanisms. FcγRs, for which four different classes are known (FcγRI, FcγRII, FcγRIII and FcγRIV), bind to the Fc region of immunoglobulin G antibodies.
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Engblom, C., Pfirschke, C. & Pittet, M. The role of myeloid cells in cancer therapies.Nat Rev Cancer16, 447–462 (2016). https://doi.org/10.1038/nrc.2016.54
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