Review
Macrophages: The Road Less Traveled, Changing Anticancer Therapy

https://doi.org/10.1016/j.molmed.2018.03.006Get rights and content

Highlights

Macrophages in tissues arise from distinct sources:

  Tissue-resident macrophages (TRMs) derive from yolk sac and fetal liver progenitors.

  Bone marrow-derived macrophages (BDMs) arise from hematopoietic stem cell.

Tissue macrophages have distinct transcriptional profiles between tissues.

Tumor-associated macrophages (TAMs) populate tumors through local proliferation of TRMs or recruitment from BDM.

Involvement of TAMs is tumor tissue specific, where TRM or BDM differentially promotes tumorigenesis depending on the tissue type.

Targeting TAMs for anticancer therapy has shown signs of preclinical and clinical success using either blunt targeting strategies (CSF-1R inhibitors) or more recently developed novel strategies such as PI3Kγ and Class IIa HDAC inhibitors.

Macrophages are present in all vertebrate tissues and have emerged as multifarious cells with complex roles in development, tissue homeostasis, and disease. Macrophages are a major constituent of the tumor microenvironment, where they either promote or inhibit tumorigenesis and metastasis depending on their state. Successful preclinical strategies to target macrophages for anticancer therapy are now being evaluated in the clinic and provide proof of concept that targeting macrophages may enhance current therapies; however, clinical success has been limited. This review discusses the promise of targeting macrophages for anticancer therapy, yet highlights how much is unknown regarding their ontogeny, regulation, and tissue-specific diversity. Further work might identify subsets of macrophages within different tissues, which could reveal novel therapeutic opportunities for anticancer therapy.

Section snippets

Tumor Macrophages in the Driver’s Seat

The immune system is composed of both adaptive and innate immune cells, which are essential to coordinate effective immune responses to protect the host from invading pathogens, bacteria, and malignant cells and to maintain homeostasis. Innate immune cells such as macrophages and dendritic cells (see Glossary) are professional antigen-presenting cells (APCs) and are the first line of defense for the host, where they engulf and present foreign material in MHC molecules Classes I and II to T

The Long and Winding Roads

Macrophages constitute 5–20% of the cells in every tissue of the body 11, 12, 13, 14 and contribute to homeostatic tissue behaviors, disease, and the TME [15]. There are various types of macrophages in tissues, which arise from at least three distinct sources: the embryonic yolk sac (YS), the fetal liver (FL), and the bone marrow (BM). Tissue-resident macrophages (TRMs) are initially derived from both the YS and the FL and reach their tissues during embryonic development, persist into

Arriving at the Destination

TRMs have multiple functions in homeostasis, host protection, and tissue injury, which are maintained at a fine balance as deregulation can lead to inflammation and disease as outlined in Table 2. Studies of gene expression and enhancer activity of TRMs have revealed distinct tissue-specific transcriptional and epigenetic programs, highlighting their specialized tissue-specific functions 41, 42, 43, 44. Transcriptional profiling of murine tissue macrophages isolated from the peritoneum, lung,

Do Tumor Macrophages Follow the Same Road-Map as TRM or BDM?

Studies of the cellular ontogeny, diversity, and tissue specificity of macrophages have revealed tissue-specific disparities, thereby provoking important questions regarding whether TAMs may also be highly diverse between tissues and/or have broad cellular ontogeny. Recent evidence has emerged that in some cancers, BDMs are recruited to the tumor and promote tumorigenesis, whereas in other tissues, TRMs proliferate and promote tumor growth and metastasis (Figure 2), as will be discussed later.

Tumor Macrophages Have Taken a Bad Detour

Macrophages can represent up to 50% of leukocytes in the TME and generally promote tumorigenesis and metastasis (Box 2). In vitro and in vivo studies have revealed that macrophages can mediate chemotherapy resistance by providing survival factors and/or activating antiapoptotic programs in malignant cancer cells 75, 76, 77. Cytotoxic therapy has been shown to induce CSF-1-dependent macrophage recruitment in a mouse model of breast cancer and inhibiting macrophage recruitment in combination with

Stop! Inhibiting Monocyte and Macrophage Recruitment to Tumor

On the basis that BM-derived monocytes are recruited to the tumor by the chemokine (C–C motif) ligand 2 (CCL2)–CCL receptor 2 (CCLR2) axis or colony-stimulating factor-1 (CSF-1)–CSF-1R signaling, inhibitors against these ligands and receptors have been developed [81]. The CCL2 [monocyte chemoattractant protein-1 (MCP-1)] is secreted by a variety of cells including monocytic, endothelial, epithelial, fibroblasts, and cancer cells. CCL2 and its receptor CCR2 are essential for recruitment of BDM

Correcting the Course: Converting TAMs to Antitumor Macrophages

Macrophages are professional APCs and have an essential role in activating T cells through cross-presentation of antigen, binding of costimulatory molecules, and secretion of cytokines, all of which are required to activate and/or promote differentiation of T cells. In the context of cancer therapy, macrophages have been shown to be required for efficacy of chemotherapy [109], programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) 110, 111, and cytotoxic

The Journey Has Only Just Begun. Future Destination: Targeting TAMs for Successful Clinical Outcome

Several open questions remain to be answered (see Outstanding Questions). The appreciation of the extent of heterogeneity of TAMs comes with new challenges and opportunities. Macrophages are no longer considered end products of a hard-wired differentiation program from monocytic precursors. Instead, TAMs have emerged as highly dynamic with both intertissue and intratissue heterogeneity. Future work will uncover subsets of TAMs, which will help define their involvement in tumorigenesis and will

Acknowledgments

The author apologizes to the authors whose work could not be cited due to space constraints. The author thanks A. Letai, J. Castrillon, and A. Mehta for insightful discussions and critical feedback. This work was supported by the National Institutes of Health grant P50CA168504 and the Friends of Dana-Farber, Dancing for a Cure.

Glossary

4-Hydroxytamoxifen (4′-OHT)
a selective estrogen receptor modulator.
Antigen-presenting cell (APC)
a cell that presents antigen in a major histocompatibility complex at its surface, a process referred to as antigen presentation. T cells can recognize this complex through their T-cell receptor.
Bone marrow (BM)
a semisolid tissue found within the spongy or cancellous portion of the bones. It is composed of HSC, marrow adipose tissue, and stromal cells.
BM-derived macrophage (BDM)
a macrophage derived

References (163)

  • M.L. Mucenski

    A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis

    Cell

    (1991)
  • W.T. Daems et al.

    Do resident macrophages proliferate?

    Immunobiology

    (1982)
  • D. Hashimoto

    Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes

    Immunity

    (2013)
  • C. Jakubzick

    Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes

    Immunity

    (2013)
  • S. Tamoutounour

    Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin

    Immunity

    (2013)
  • E. Zigmond

    Ly6Chi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells

    Immunity

    (2012)
  • G. Kovtunovych

    Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution

    Blood

    (2010)
  • M. Haldar

    Heme-mediated SPI-C induction promotes monocyte differentiation into iron-recycling macrophages

    Cell

    (2014)
  • D. Gosselin

    Environment drives selection and function of enhancers controlling tissue-specific macrophage identities

    Cell

    (2014)
  • Y. Lavin

    Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment

    Cell

    (2014)
  • R.L. Bowman

    Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies

    Cell Rep.

    (2016)
  • M. De Palma

    Origins of brain tumor macrophages

    Cancer Cell

    (2016)
  • A. Hameed

    Immunohistochemical expression of CD68 antigen in human peripheral blood T cells

    Hum. Pathol.

    (1994)
  • T. Tsujikawa

    Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis

    Cell Rep.

    (2017)
  • M. Broz

    Dissecting the tumor myeloid compartment reveals rare activating antigen presenting cells, critical for T cell immunity

    Cancer Cell

    (2014)
  • M. Castells

    Ovarian ascites-derived Hospicells promote angiogenesis via activation of macrophages

    Cancer Lett.

    (2012)
  • A.L. Correia et al.

    The tumor microenvironment is a dominant force in multidrug resistance

    Drug Resist. Updat.

    (2012)
  • C.H. Ries

    Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy

    Cancer Cell

    (2014)
  • J. Zhang

    Multiple roles of chemokine (C–C motif) ligand 2 in promoting prostate cancer growth

    J. Natl. Cancer Inst.

    (2010)
  • F. Moisan

    Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers

    Mol. Oncol.

    (2014)
  • K.P. MacDonald

    An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation

    Blood

    (2010)
  • P.A. Cassier

    CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study

    Lancet Oncol.

    (2015)
  • G. Germano

    Role of macrophage targeting in the antitumor activity of trabectedin

    Cancer Cell

    (2013)
  • J.E. Smith-Garvin

    T cell activation

    Annu. Rev. Immunol.

    (2009)
  • G. Solinas

    Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation

    J. Leukoc. Biol.

    (2009)
  • J.W. Pollard

    Tumour-educated macrophages promote tumour progression and metastasis

    Nat. Rev. Cancer

    (2004)
  • M. Erreni

    Tumor-associated macrophages (TAM) and inflammation in colorectal cancer

    Cancer Microenviron.

    (2011)
  • C. Engblom

    The role of myeloid cells in cancer therapies

    Nat. Rev. Cancer

    (2016)
  • D.A. Hume et al.

    Mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. Identification of resident macrophages in renal medullary and cortical interstitium and the juxtaglomerular complex

    J. Exp. Med.

    (1983)
  • D.A. Hume

    The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80. Relationship between macrophages, Langerhans cells, reticular cells, and dendritic cells in lymphoid and hematopoietic organs

    J. Exp. Med.

    (1983)
  • D.A. Hume

    Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers

    J. Cell Biol.

    (1983)
  • E. Gomez Perdiguero

    Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors

    Nature

    (2015)
  • C. Schulz

    A lineage of myeloid cells independent of Myb and hematopoietic stem cells

    Science

    (2012)
  • J. Hopkinson-Woolley

    Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse

    J. Cell Sci.

    (1994)
  • F. Geissmann

    Development of monocytes, macrophages, and dendritic cells

    Science

    (2010)
  • K. Jung

    Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

    J. Clin. Invest.

    (2017)
  • F.K. Swirski

    Identification of splenic reservoir monocytes and their deployment to inflammatory sites

    Science

    (2009)
  • K. Jung

    Targeting CXCR4-dependent immunosuppressive Ly6C(low) monocytes improves antiangiogenic therapy in colorectal cancer

    Proc. Natl. Acad. Sci. U. S. A.

    (2017)
  • N.V. Serbina

    Monocyte-mediated defense against microbial pathogens

    Annu. Rev. Immunol.

    (2008)
  • F. Ginhoux

    Fate mapping analysis reveals that adult microglia derive from primitive macrophages

    Science

    (2010)
  • Cited by (202)

    View all citing articles on Scopus
    View full text