Identifying the infiltrators Elisa Gomez Perdiguero and Frederic Geissmann Science 344, 801 (2014); DOI: 10.1126/science.1255117
This copy is for your personal, non-commercial use only.
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of May 24, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/344/6186/801.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/344/6186/801.full.html#related This article cites 16 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/344/6186/801.full.html#ref-list-1 This article appears in the following subject collections: Immunology http://www.sciencemag.org/cgi/collection/immunology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
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stress environment appear to be critical for synthesizing this phase. So why has this new transition not been observed seismically? One possibility is that the velocity change across the transition may be too small and/or the boundary may undulate dramatically in its depth. Alternatively, the temperature of the deep mantle may lie below the temperature of the disproportionation reaction [which would require that the mantle be a few hundred kelvin cooler than currently inferred (12)—but this would also imply that disproportionation could have been important in the hotter past]. Another option is that the oxidation state of iron in the mantle may differ from those within the experiments. The provocative aspects of this discovery include not just changing the possible mineralogy of the deeper lower mantle, but also that two phases of markedly different densities are produced. Whether these phases could undergo partial segregation, thus enriching or depleting regions in the H-phase (particularly in an earlier, hotter, less viscous, and possibly partially molten mantle), is unknown. If such segregation did occur, a natural explanation for the genesis of LLSVPs might exist. Depending on its elasticity, an enrichment of H-phase within these regions might provide an avenue to explain their anomalous seismic signature. Each of these experiments is the direct result of developments in high-pressure, hightemperature techniques and the availability of high-intensity synchrotron sources. Probing the sensitivity of the pressure and temperature of melting and the phase transition to variable oxygen fugacities, shifts in major and minor elemental abundances, and volatile contents holds the prospect of mapping out the likely chemical behavior of the lower mantle. In doing so, the current void of information on the differentiation processes that govern the chemical variations, structural features, and evolution of Earth’s deepest rocky reaches will be filled. ■ REFERENCES
1. 2. 3. 4. 5.
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
6. 7. 8. 9. 10. 11. 12.
J. Austermann et al., Geophys. J. Int. 197, 1 (2014). D. Andrault et al., Science 344, 892 (2014). L. Zhang et al., Science 344, 877 (2014). S. Ni, D. V. Helmberger, J. Tromp, Geophys. J. Int. 161, 283 (2005). M. Wysession et al., in The Core-Mantle Boundary Region, M. Gurnis, M. Wysession, E. Knittle, B. Buffett, Eds., Geodyn. Ser. (American Geophysical Union, Washington, DC, 1998), vol. 28, 319–334. M. S. Thorne, E. J. Garnero, G. Jahnke, H. Igel, A. K. McNamara, Earth Planet. Sci. Lett. 364, 59 (2013). J. F. Lin et al., Rev. Geophys. 51, 244 (2013). F. Deschamps, L. Cobden, P. J. Tackley, Earth Planet. Sci. Lett. 349-350, 198 (2012). M. Murakami et al., Science 304, 855 (2004). S. Rost et al., Nature 435, 666 (2005). S. Anzellini et al., Science 340, 464 (2013). T. Katsura, A. Yoneda, D. Yamazaki, T. Yoshino, E. Ito, Phys. Earth Planet. Inter. 183, 212 (2010). 10.1126/science.1254399
CANCER IMMUNOLOGY
Identifying the infiltrators Molecular characterization of macrophages reveals distinct types during tumorigenesis By Elisa Gomez Perdiguero and Frederic Geissmann
T
he mammalian immune system both suppresses and tolerates tumors, so understanding this complexity should benefit the development of cancer therapies. Macrophages are proposed to play an important role in suppressing the immune response to cancer cells, but it is not clear where these immune cells come from or whether there are distinct populations of macrophages with specific roles in this setting. On page 921 of this issue, Franklin et al. (1) forge a more coherent view of macrophages that are associated with tumor growth by assessing their origin, phenotype, and functions in an animal model of breast cancer. Tumor progression can be divided into three phases—initiation, growth, and metastasis (see the figure). The first phase is characterized by the cell-autonomous accumulation of genetic defects that leads to cell transformation. This is followed by clonal growth of transformed cells within the tissue—the primary tumor site (2). Metastasis results from the successful “engraftment” of circulating tumor cells into secondary locations where they proliferate after a dormancy phase in which metastatic cells remain quiescent (3). In both primary and secondary tumor sites, the stroma, which includes mesenchymal cells, macrophages, and extracellular matrix (3), is thought to play a role in the initial survival and proliferation of transformed cells. However, as a solid tumor grows and tumor cells acquire the potential to escape the primary site, the stroma becomes a more complex environment, with newly formed blood and lymphatic vessels and the recruitment and/or proliferation of lymphoid and myeloid immune cells (4). Immune cells are proposed to prevent tumor progression via the elimination of immunogenic tumor cells by T lymphocytes (CD8 subtype), a phenomenon known as immunosurveillance (also called immunoediting). During this process, tumors that display either reduced immunogenicity or enhanced immunosuppressive activity will escape elimination (5). Macrophages present in the tumor site can activate the immune response, but are mainly
SCIENCE sciencemag.org
thought to contribute to immunosuppression and tumor progression (6, 7), particularly in the mammary gland (8). A high density of macrophages in tumors is also associated with worse overall survival in patients with gastric, urogenital, and head and neck cancers, although it seems to be associated with better overall survival in patients with colorectal cancer (7). Franklin et al. carefully explore the contribution of macrophages to tumor growth in mice that develop a mammary cancer
that is genetically driven by the expression of an oncogene. In investigating the development and differentiation of macrophages in the normal mammary gland and during the progression of a mammary tumor, the authors identify a population of macrophages that accumulates during tumor growth called tumor-associated macrophages (TAMs). These cells develop from bone marrow–derived cells with the characteristics of inflammatory monocytes, which are recruited to the tumor where they differentiate into macrophages and subsequently proliferate. Franklin et al. observed that when signaling by the protein Notch is prevented in these TAMs, their differentiation is blocked. Interestingly, TAMs are distinct from macrophages present in normal mammary tissue, which develop independently of Notch signaling. Depletion of TAMs led to a reduced tumor burden in the animal and increased the cytotoxic potential of T lymphocytes present in the primary tumor site. Thus, monocyte-derived Notch-dependent TAMs are critical for tumor growth in this mammary gland tumor model, at least in 23 MAY 2014 • VOL 344 ISSUE 6186
Published by AAAS
801
INSIGHTS | P E R S P E C T I V E S
Primary tumor site Mammary gland
Secondary tumor site Brain, lung, liver, bones
Tumor growth
Tumor-associated macrophages Resident macrophages
al rviv Su Proliferation of tumor-associated macrophages (Notch-dependent)
Meta stas is
T cells
Tumor cell (genetic damage)
Bone marrow monocytes Tumor-associated macrophages. Three stages of tumor progression are shown. Origin and role of TAMs in mammary gland tumors are depicted in the central area. The roles of tissue-resident macrophages and tumor-associated macrophages during initiation stage and the metastatic process are not yet known.
Center for Molecular and Cellular Biology of Infammation – CMCBI, Division of Immunology Infection & Infammatory Diseases, King’s College London, UK. E-mail: frederic. [email protected]
802
The possible roles of Notch-dependent monocyte-derived TAMs in tumor initiation, angiogenesis, and the metastatic process were not investigated by Franklin et al. A role for monocytes in the metastasis of mammary tumors was proposed (11), and the blockade of delta-like 4 (a Notch ligand) was shown to inhibit tumor growth by promoting nonproductive angiogenesis (12). Therefore, it would be interesting to further investigate the roles of Notch-dependent monocyte-derived TAMs in these processes. Franklin et al. report that mammary tissue macrophages (MTMs) present in the tissue in a steady state, and distinct from TAMs, also originate from monocytes but continuously renew in a Notch-independent manner. MTM numbers decrease during tumor progression. Their depletion did not impact tumor burden in the animal. It will be interesting to investigate whether this is also the case in nonmammary tumors or at the site of metastasis, in particular, in tissues such as the liver, epidermis, and brain where resident macrophages do not derive from monocytes. Many tissue-resident macrophages such as Kupffer cells in the liver, Langerhans cells in the epidermis, and microglia in the brain develop during embryogenesis and persist into adulthood independently from hematopoietic stem cells and monocytes (13). Activation of Kupffer cells by a cell surface protein called triggering receptor expressed on myeloid cells 1 (TREM-1) (ligand is unknown) was proposed to promote the development of hepatocellular carcinoma (14). Langerhans cells can metabolize chemicals into metabolites that induce DNA damage in
epithelial cells and promote squamous cell carcinoma (15). By contrast, microglia were proposed to suppress brain tumor-initiating cells in the genesis or recurrence of gliomas (16). Resident macrophages thus could be involved in tumor initiation or modulate the ability of metastatic tumor cells to engraft or escape dormancy. Furthermore, it would be interesting to investigate whether resident macrophages contribute to tumor growth alongside monocyte-derived TAMs outside the mammary gland. Tumor macrophages were long suspected to play important, but seemingly complex, roles in tumor progression. The characterization of monocyte-derived TAMs in the growth of mammary tumors is an important step toward a molecular characterization of the role of macrophages in cancer biology. This may open up opportunities to target TAM-specific properties to treat cancer. ■ REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
R. A. Franklin et al., Science 344, 921 (2014). D. Hanahan, R. A. Weinberg, Cell 100, 57 (2000). T. Oskarsson et al., Cell Stem Cell 14, 306 (2014). B. S. Wiseman, Z. Werb, Science 296, 1046 (2002). H. Matsushita et al., Nature 482, 400 (2012). T. A. Wynn et al., Nature 496, 445 (2013). Q. W. Zhang et al., PLOS ONE 7, e50946 (2012). L. M. Coussens, J. W. Pollard, Cold Spring Harb. Perspect. Biol. 3, a003285 (2011). E. Van Overmeire et al., Front. Immunol. 5, 127 (2014). A. Mantovani, A. Sica, Curr. Opin. Immunol. 22, 231 (2010). B. Z. Qian et al., Nature 475, 222 (2011). I. Noguera-Troise et al., Nature 444, 1032 (2006). C. Schulz et al., Science 336, 86 (2012). J. Wu et al., Cancer Res. 72, 3977 (2012). B. G. Modi et al., Science 335, 104 (2012). S. Sarkar et al., Nat. Neurosci. 17, 46 (2014).
10.1126/science.1255117
sciencemag.org SCIENCE
23 MAY 2014 • VOL 344 ISSUE 6186
Published by AAAS
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
part through the inhibition of a lymphocytemediated immune response. A current model proposes that the activation state of TAMs and their contribution to tumor growth depends on the stage of tumor development (6, 9, 10). Macrophages are activated by a range of factors including a variety of cytokines, producing different phenotypes. The classical phenotype is known as the “M1” macrophage, which is driven by interferon-γ (IFN-γ) and T helper cells (TH1 subtype) and is associated with inflammation and tissue destruction. The alternative phenotype, called the “M2” macrophage, is driven by interleukin 4 (IL-4) and TH2 cells and is associated with tissue repair and remodeling. To which category do TAMs belong? Early-stage tumor macrophage infiltrates have been reported with an M1 phenotype, which could result in tumor elimination (9). However, early-stage M1 macrophages also have been reported to favor tumor promotion (9). And in latestage established tumors, an M2 phenotype has been observed, associated with T cell inhibition and tumor growth (8–10). Franklin et al. indicate that monocyte-derived Notchdependent TAMs in a mammary tumor have neither an M1 nor an M2 gene expression profile and are independent of IL-4 signaling, although they promote tumor growth and inhibit a T cell immune response. This suggests that M1-M2 polarization of macrophages is not essential for TAM functions, at least in this model of mammary cancer.
This copy is for your personal, non-commercial use only.
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of May 24, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/344/6186/801.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/344/6186/801.full.html#related This article cites 16 articles, 5 of which can be accessed free: http://www.sciencemag.org/content/344/6186/801.full.html#ref-list-1 This article appears in the following subject collections: Immunology http://www.sciencemag.org/cgi/collection/immunology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2014 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on May 24, 2014
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
stress environment appear to be critical for synthesizing this phase. So why has this new transition not been observed seismically? One possibility is that the velocity change across the transition may be too small and/or the boundary may undulate dramatically in its depth. Alternatively, the temperature of the deep mantle may lie below the temperature of the disproportionation reaction [which would require that the mantle be a few hundred kelvin cooler than currently inferred (12)—but this would also imply that disproportionation could have been important in the hotter past]. Another option is that the oxidation state of iron in the mantle may differ from those within the experiments. The provocative aspects of this discovery include not just changing the possible mineralogy of the deeper lower mantle, but also that two phases of markedly different densities are produced. Whether these phases could undergo partial segregation, thus enriching or depleting regions in the H-phase (particularly in an earlier, hotter, less viscous, and possibly partially molten mantle), is unknown. If such segregation did occur, a natural explanation for the genesis of LLSVPs might exist. Depending on its elasticity, an enrichment of H-phase within these regions might provide an avenue to explain their anomalous seismic signature. Each of these experiments is the direct result of developments in high-pressure, hightemperature techniques and the availability of high-intensity synchrotron sources. Probing the sensitivity of the pressure and temperature of melting and the phase transition to variable oxygen fugacities, shifts in major and minor elemental abundances, and volatile contents holds the prospect of mapping out the likely chemical behavior of the lower mantle. In doing so, the current void of information on the differentiation processes that govern the chemical variations, structural features, and evolution of Earth’s deepest rocky reaches will be filled. ■ REFERENCES
1. 2. 3. 4. 5.
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
6. 7. 8. 9. 10. 11. 12.
J. Austermann et al., Geophys. J. Int. 197, 1 (2014). D. Andrault et al., Science 344, 892 (2014). L. Zhang et al., Science 344, 877 (2014). S. Ni, D. V. Helmberger, J. Tromp, Geophys. J. Int. 161, 283 (2005). M. Wysession et al., in The Core-Mantle Boundary Region, M. Gurnis, M. Wysession, E. Knittle, B. Buffett, Eds., Geodyn. Ser. (American Geophysical Union, Washington, DC, 1998), vol. 28, 319–334. M. S. Thorne, E. J. Garnero, G. Jahnke, H. Igel, A. K. McNamara, Earth Planet. Sci. Lett. 364, 59 (2013). J. F. Lin et al., Rev. Geophys. 51, 244 (2013). F. Deschamps, L. Cobden, P. J. Tackley, Earth Planet. Sci. Lett. 349-350, 198 (2012). M. Murakami et al., Science 304, 855 (2004). S. Rost et al., Nature 435, 666 (2005). S. Anzellini et al., Science 340, 464 (2013). T. Katsura, A. Yoneda, D. Yamazaki, T. Yoshino, E. Ito, Phys. Earth Planet. Inter. 183, 212 (2010). 10.1126/science.1254399
CANCER IMMUNOLOGY
Identifying the infiltrators Molecular characterization of macrophages reveals distinct types during tumorigenesis By Elisa Gomez Perdiguero and Frederic Geissmann
T
he mammalian immune system both suppresses and tolerates tumors, so understanding this complexity should benefit the development of cancer therapies. Macrophages are proposed to play an important role in suppressing the immune response to cancer cells, but it is not clear where these immune cells come from or whether there are distinct populations of macrophages with specific roles in this setting. On page 921 of this issue, Franklin et al. (1) forge a more coherent view of macrophages that are associated with tumor growth by assessing their origin, phenotype, and functions in an animal model of breast cancer. Tumor progression can be divided into three phases—initiation, growth, and metastasis (see the figure). The first phase is characterized by the cell-autonomous accumulation of genetic defects that leads to cell transformation. This is followed by clonal growth of transformed cells within the tissue—the primary tumor site (2). Metastasis results from the successful “engraftment” of circulating tumor cells into secondary locations where they proliferate after a dormancy phase in which metastatic cells remain quiescent (3). In both primary and secondary tumor sites, the stroma, which includes mesenchymal cells, macrophages, and extracellular matrix (3), is thought to play a role in the initial survival and proliferation of transformed cells. However, as a solid tumor grows and tumor cells acquire the potential to escape the primary site, the stroma becomes a more complex environment, with newly formed blood and lymphatic vessels and the recruitment and/or proliferation of lymphoid and myeloid immune cells (4). Immune cells are proposed to prevent tumor progression via the elimination of immunogenic tumor cells by T lymphocytes (CD8 subtype), a phenomenon known as immunosurveillance (also called immunoediting). During this process, tumors that display either reduced immunogenicity or enhanced immunosuppressive activity will escape elimination (5). Macrophages present in the tumor site can activate the immune response, but are mainly
SCIENCE sciencemag.org
thought to contribute to immunosuppression and tumor progression (6, 7), particularly in the mammary gland (8). A high density of macrophages in tumors is also associated with worse overall survival in patients with gastric, urogenital, and head and neck cancers, although it seems to be associated with better overall survival in patients with colorectal cancer (7). Franklin et al. carefully explore the contribution of macrophages to tumor growth in mice that develop a mammary cancer
that is genetically driven by the expression of an oncogene. In investigating the development and differentiation of macrophages in the normal mammary gland and during the progression of a mammary tumor, the authors identify a population of macrophages that accumulates during tumor growth called tumor-associated macrophages (TAMs). These cells develop from bone marrow–derived cells with the characteristics of inflammatory monocytes, which are recruited to the tumor where they differentiate into macrophages and subsequently proliferate. Franklin et al. observed that when signaling by the protein Notch is prevented in these TAMs, their differentiation is blocked. Interestingly, TAMs are distinct from macrophages present in normal mammary tissue, which develop independently of Notch signaling. Depletion of TAMs led to a reduced tumor burden in the animal and increased the cytotoxic potential of T lymphocytes present in the primary tumor site. Thus, monocyte-derived Notch-dependent TAMs are critical for tumor growth in this mammary gland tumor model, at least in 23 MAY 2014 • VOL 344 ISSUE 6186
Published by AAAS
801
INSIGHTS | P E R S P E C T I V E S
Primary tumor site Mammary gland
Secondary tumor site Brain, lung, liver, bones
Tumor growth
Tumor-associated macrophages Resident macrophages
al rviv Su Proliferation of tumor-associated macrophages (Notch-dependent)
Meta stas is
T cells
Tumor cell (genetic damage)
Bone marrow monocytes Tumor-associated macrophages. Three stages of tumor progression are shown. Origin and role of TAMs in mammary gland tumors are depicted in the central area. The roles of tissue-resident macrophages and tumor-associated macrophages during initiation stage and the metastatic process are not yet known.
Center for Molecular and Cellular Biology of Infammation – CMCBI, Division of Immunology Infection & Infammatory Diseases, King’s College London, UK. E-mail: frederic. [email protected]
802
The possible roles of Notch-dependent monocyte-derived TAMs in tumor initiation, angiogenesis, and the metastatic process were not investigated by Franklin et al. A role for monocytes in the metastasis of mammary tumors was proposed (11), and the blockade of delta-like 4 (a Notch ligand) was shown to inhibit tumor growth by promoting nonproductive angiogenesis (12). Therefore, it would be interesting to further investigate the roles of Notch-dependent monocyte-derived TAMs in these processes. Franklin et al. report that mammary tissue macrophages (MTMs) present in the tissue in a steady state, and distinct from TAMs, also originate from monocytes but continuously renew in a Notch-independent manner. MTM numbers decrease during tumor progression. Their depletion did not impact tumor burden in the animal. It will be interesting to investigate whether this is also the case in nonmammary tumors or at the site of metastasis, in particular, in tissues such as the liver, epidermis, and brain where resident macrophages do not derive from monocytes. Many tissue-resident macrophages such as Kupffer cells in the liver, Langerhans cells in the epidermis, and microglia in the brain develop during embryogenesis and persist into adulthood independently from hematopoietic stem cells and monocytes (13). Activation of Kupffer cells by a cell surface protein called triggering receptor expressed on myeloid cells 1 (TREM-1) (ligand is unknown) was proposed to promote the development of hepatocellular carcinoma (14). Langerhans cells can metabolize chemicals into metabolites that induce DNA damage in
epithelial cells and promote squamous cell carcinoma (15). By contrast, microglia were proposed to suppress brain tumor-initiating cells in the genesis or recurrence of gliomas (16). Resident macrophages thus could be involved in tumor initiation or modulate the ability of metastatic tumor cells to engraft or escape dormancy. Furthermore, it would be interesting to investigate whether resident macrophages contribute to tumor growth alongside monocyte-derived TAMs outside the mammary gland. Tumor macrophages were long suspected to play important, but seemingly complex, roles in tumor progression. The characterization of monocyte-derived TAMs in the growth of mammary tumors is an important step toward a molecular characterization of the role of macrophages in cancer biology. This may open up opportunities to target TAM-specific properties to treat cancer. ■ REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
R. A. Franklin et al., Science 344, 921 (2014). D. Hanahan, R. A. Weinberg, Cell 100, 57 (2000). T. Oskarsson et al., Cell Stem Cell 14, 306 (2014). B. S. Wiseman, Z. Werb, Science 296, 1046 (2002). H. Matsushita et al., Nature 482, 400 (2012). T. A. Wynn et al., Nature 496, 445 (2013). Q. W. Zhang et al., PLOS ONE 7, e50946 (2012). L. M. Coussens, J. W. Pollard, Cold Spring Harb. Perspect. Biol. 3, a003285 (2011). E. Van Overmeire et al., Front. Immunol. 5, 127 (2014). A. Mantovani, A. Sica, Curr. Opin. Immunol. 22, 231 (2010). B. Z. Qian et al., Nature 475, 222 (2011). I. Noguera-Troise et al., Nature 444, 1032 (2006). C. Schulz et al., Science 336, 86 (2012). J. Wu et al., Cancer Res. 72, 3977 (2012). B. G. Modi et al., Science 335, 104 (2012). S. Sarkar et al., Nat. Neurosci. 17, 46 (2014).
10.1126/science.1255117
sciencemag.org SCIENCE
23 MAY 2014 • VOL 344 ISSUE 6186
Published by AAAS
ILLUSTRATION: V. ALTOUNIAN/SCIENCE
part through the inhibition of a lymphocytemediated immune response. A current model proposes that the activation state of TAMs and their contribution to tumor growth depends on the stage of tumor development (6, 9, 10). Macrophages are activated by a range of factors including a variety of cytokines, producing different phenotypes. The classical phenotype is known as the “M1” macrophage, which is driven by interferon-γ (IFN-γ) and T helper cells (TH1 subtype) and is associated with inflammation and tissue destruction. The alternative phenotype, called the “M2” macrophage, is driven by interleukin 4 (IL-4) and TH2 cells and is associated with tissue repair and remodeling. To which category do TAMs belong? Early-stage tumor macrophage infiltrates have been reported with an M1 phenotype, which could result in tumor elimination (9). However, early-stage M1 macrophages also have been reported to favor tumor promotion (9). And in latestage established tumors, an M2 phenotype has been observed, associated with T cell inhibition and tumor growth (8–10). Franklin et al. indicate that monocyte-derived Notchdependent TAMs in a mammary tumor have neither an M1 nor an M2 gene expression profile and are independent of IL-4 signaling, although they promote tumor growth and inhibit a T cell immune response. This suggests that M1-M2 polarization of macrophages is not essential for TAM functions, at least in this model of mammary cancer.
