Elsevier

Cellular Immunology

Volume 330, August 2018, Pages 188-201
Cellular Immunology

Review article
Myeloid cell heterogeneity in cancer: not a single cell alike

https://doi.org/10.1016/j.cellimm.2018.02.008Get rights and content

Highlights

  • Differences in ontogeny, activation status and localization drive the generation of diverse myeloid cell phenotypes in tumors.

  • Unsupervised high-dimensional analysis of tumor-infiltrating macrophages in human tumors revealed a large number of subpopulations that do not correspond to M1/M2 polarization.

  • Lack of highly specific myeloid-derived suppressor cell (MDSC) markers impedes the dissection of functional differences between mature monocytes/neutrophils versus immature MDSCs.

  • Ontogenically distinct tumor-infiltrating dendritic cell subsets show differential effects on antitumor immunity and immunotherapy.

  • High-dimensional analytical tools that preserve spatial information are needed to better unveil the impact of localization on myeloid cell heterogeneity.

Abstract

Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on antitumor immunity and influence fundamental processes that underlie malignancy, including neoangiogenesis, sustained cancer cell proliferation, metastasis and therapy resistance. For these reasons, development of therapeutic approaches to deplete or reprogram myeloid cells in cancer is an emerging field of interest. However, knowledge about the heterogeneity of myeloid cells in tumors and their variability between patients and disease stages is still limited. In this review, we summarize the most recent advances in our understanding about how the phenotype of tumor-associated macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells is dictated by their ontogeny, activation status and localization. We also outline major open questions that will only be resolved by applying high-dimensional single-cell technologies and systems biology approaches in the analysis of the tumor microenvironment.

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.

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