Review articleMyeloid cell heterogeneity in cancer: not a single cell alike
Introduction
One of the most fundamental – albeit long overlooked – aspects of cancer is that the tumor is as complex, if not more so, as the normal tissue from which it has emerged. A careful look at the histological structure of tumor tissue reveals the presence of stromal cells, including immune cells, connective tissue cells and vascular components, collectively termed as the “tumor microenvironment” (TME). The heterotypic interactions between the TME and neoplastic cells have an enormous impact on tumor progression from carcinogenesis to metastatic dissemination [1]. The immune component of the TME gained prominence in the last decade with the realization that suppressed intratumoral T lymphocytes can be reactivated by inhibiting certain immune checkpoints, unleashing antitumor cytotoxic T lymphocyte (CTL) responses [2]. Therapeutic antibodies inhibiting immune checkpoints yielded remarkable long-lasting clinical responses in some patients, revolutionizing cancer therapy [2]. Beside T lymphocytes, a large fraction of tumor-associated leukocytes is made up of myeloid cells, dominantly macrophages and neutrophils at varying stages of differentiation. These myeloid cells have been shown to promote virtually all steps of tumor progression including carcinogenesis, tumor angiogenesis, cancer cell proliferation and invasion as well as colonization of metastatic sites [1], [3]. Myeloid cells are also central determinants of the immunosuppressive microenvironment that prevents efficient T-cell infiltration into tumors and decreases the ability of intratumoral T cells to recognize and kill cancer cells, ultimately posing a major obstacle to efficient immunotherapies [4]. In addition, the presence of myeloid cells contributes to the emergence of resistance to chemotherapy, radiotherapy, anti-angiogenic therapy and targeted therapies [3], [5], [6]. Thus, given the general abundance of myeloid cells in tumors, their apparent disease-promoting functions and the fact that, unlike cancer cells, they are genetically stable, myeloid cells offer an attractive therapeutic target. This notion triggered the development of numerous therapeutic approaches that deplete or reprogram myeloid cells in order to inhibit their immunosuppressive effect in tumors, yielding some encouraging preclinical results and initiation of clinical trials [1], [7], [8]. Nevertheless, presence of immunostimulatory antigen-presenting myeloid cells, dendritic cells in particular, is instrumental for the initiation of antitumor immunity. Therefore, novel therapeutic avenues that facilitate presentation of tumor antigens and priming of tumor-specific CTLs by antigen-presenting cells (APCs) are being actively pursued as well [9]. Myeloid cells are generally very efficient in adapting their phenotype according to perceived tissue cues in order to orchestrate a suitable functional response. The unique features of tumors, such as hypoxia, necrosis, the altered metabolic state of neoplastic cells and the presence of activated stromal cells creates a complex tissue milieu, presumably driving the emergence of myeloid cell phenotypes that cannot be found in normal tissues. Unravelling the true diversity of these phenotypes is indispensable for the design of novel diagnostic and therapeutic tools. Discovering subpopulations with differential – perhaps even opposing – effects on disease progression will pave the way toward more selective therapeutic approaches. This will also require the identification of population-specific markers which will enable selective targeting of certain cell types and can serve as biomarkers predicting therapy responses. In this review, we will describe the most recent advances in our understanding regarding the diversity of myeloid cells in tumors and will also attempt to highlight some of the most important open questions. We will focus on tumor-infiltrating macrophages, monocytes, neutrophils, myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs), as the phenotypic heterogeneity of eosinophils, basophils and mast cells has not been studied in detail yet [3]. The main factors that primarily account for myeloid cell heterogeneity are their ontogeny, activation status and localization. Although these factors are very likely to interact at several levels, here we will address them separately for clarity.
Section snippets
Macrophages
Macrophages are essential in shaping the tissue architecture during development and continue to maintain tissue homeostasis after birth [10]. Although their trophic functions are crucial in restoring tissue integrity, maladaptive macrophage responses contribute to the pathogenesis of numerous diseases, including atherosclerosis, chronic fibrosis, neurodegeneration and cancer [10]. Clinical tumor specimens show abundant presence of these CD68+ tumor-associated macrophages (TAMs), and their
Monocytes, neutrophils and myeloid-derived suppressor cells
Monocytes and neutrophils not only act as circulating precursors for tumor-infiltrating myeloid cells but are also greatly affected by soluble factors released by the tumor into the systemic circulation. Tumor-derived factors, including cytokines, chemokines and metabolites alter normal hematopoiesis and promote the expansion of immature monocytes and neutrophils with strong immunosuppressive features, collectively termed as myeloid-derived suppressor cells (MDSCs) [87]. These suppressive
Dendritic cells
DCs are professional pathogen sensing, phagocytosing and antigen-presenting cells present in all tissues, including the TME [127]. DCs are essential regulators of the innate and adaptive immune response in cancer, as these cells have the ability to present tumor-associated antigens to T cells and have hence an essential role in licensing anti-tumor CTLs to eradicate tumor cells [128]. In this respect, tumor-associated DCs (TADCs) constitute an essential target in efforts to generate therapeutic
Future directions and novel approaches to decipher myeloid cell heterogeneity in cancer
Studies from the last decade using mainly microscopy and flow cytometry have suggested the presence of a remarkable heterogeneity of myeloid cells in cancer. While these tools offer high spatial or cellular resolution, they rely on a limited number of established markers. Consequently, analysis of cell types defined through these methods involves pooling thousands to millions of cells isolated based on the expression of a few markers. In the past years, new high-dimensional data acquisition
Acknowledgments
The authors apologize to those researchers whose work could not be cited due to space restrictions. We thank Prof. Jo Van Ginderachter, Dr. Jiri Keirsse, Evangelia Bolli, Aleksandar Murgaski and Xenia Geeraerts for discussions on this topic. MK is supported by a PhD grant from the Research Foundation Flanders (FWO). SVG is supported by the Flanders Agency for Innovation by Science and Technology (IWT). KM is supported by the Brains back to Brussels grant by Innoviris. YS is an ISAC Marylou
Conflict of Interest
The authors have declared that no conflict of interest exists.
References (171)
- et al.
Accessories to the crime: functions of cells recruited to the tumor microenvironment
Cancer Cell
(2012) - et al.
Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential
Cell
(2015) - et al.
Macrophage regulation of tumor responses to anticancer therapies
Cancer Cell
(2013) - et al.
Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade
Cell Rep.
(2017) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues
Blood
(2004)- et al.
Mononuclear phagocyte heterogeneity in cancer: different subsets and activation states reaching out at the tumor site
Immunobiology
(2011) - et al.
Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal
Cell
(2013) - et al.
Origin and functions of tissue macrophages
Immunity
(2014) - et al.
Tissue-resident macrophage ontogeny and homeostasis
Immunity
(2016) - et al.
Environment drives selection and function of enhancers controlling tissue-specific macrophage identities
Cell
(2014)
Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment
Cell
Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression
Cancer Cell
Transcriptome-based network analysis reveals a spectrum model of human macrophage activation
Immunity
Mass cytometry: single cells many features
Cell
Data-driven phenotypic dissection of aml reveals progenitor-like cells that correlate with prognosis
Cell
Tumor microenvironmental physiology and its implications for radiation oncology
Semin. Radiat. Oncol.
The multifaceted role of perivascular macrophages in tumors
Cancer Cell
Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction
Blood
Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells
Cancer Cell
Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity
Cancer Cell
L-arginine metabolism in myeloid cells controls T-lymphocyte functions
Trends Immunol.
Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia
Cancer Cell
Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity
Blood
Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer
Cell Rep.
The role of myeloid cells in cancer therapies
Nat. Rev. Cancer
Coordinated regulation of myeloid cells by tumours
Nat. Rev. Immunol.
Reprogramming of tumor-associated macrophages with anticancer therapies: radiotherapy versus chemo- and immunotherapies
Front. Immunol.
Tumour-associated macrophages as treatment targets in oncology
Nat. Rev. Clin. Oncol.
Antunes, et al., Beyond the M-CSF receptor – novel therapeutic targets in tumor-associated macrophages
FEBS J.
Exploiting tumor-associated dendritic cell heterogeneity for novel cancer therapies
J. Leukoc. Biol.
Macrophage biology in development, homeostasis and disease
Nature
Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature
PLoS ONE
The cancer genome atlas pan-cancer analysis project
Nat. Genet.
Computational genomics tools for dissecting tumour-immune cell interactions
Nat. Rev. Genet.
The prognostic landscape of genes and infiltrating immune cells across human cancers
Nat. Med.
Novel insights in the regulation and function of macrophages in the tumor microenvironment
Curr. Opin. Oncol.
Mechanisms driving macrophage diversity and specialization in distinct tumor microenvironments and parallelisms with other tissues
Front. Immunol.
Monocyte differentiation and antigen-presenting functions
Nat. Rev. Immunol.
Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior
Science
Patrolling monocytes control tumor metastasis to the lung
Science
Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy
J. Clin. Invest.
Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment
BBA
Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages
Nat. Immunol.
Specification of tissue-resident macrophages during organogenesis
Science.
Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells
Nat. Commun.
Yolk Sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages
Immunity
Does niche competition determine the origin of tissue-resident macrophages?
Nat. Rev. Immunol.
Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies
Cell Rep.
Cellular and molecular identity of tumor-associated macrophages in glioblastoma
Cancer Res.
Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq
Science
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