Trends in Molecular Medicine
ReviewMacrophages: The Road Less Traveled, Changing 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
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