Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes (monocyte-derived macrophages) or yolk sac progenitors (tissue-resident macrophages), but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.
Although there is some debate, most evidence suggests that TAMs have a tumor-promoting phenotype. TAMs affect most aspects of tumor cell biology and drive pathological phenomena including tumor cell proliferation, tumor angiogenesis, invasion and metastasis, immunosuppression, and drug resistance.
Tumor angiogenesis is the process by which a tumor forms new blood vessels in order to maintain a supply of nutrients and oxygen and to grow beyond a few millimeters in size. The formation of vasculature also facilitates the escape of malignant cells into blood circulation and the onset of metastasis. One of the primary tumor-promoting mechanisms of TAMs is the secretion of potent pro-angiogenic factors. The most highly expressed and well-characterized angiogenic factor produced by TAMs is vascular endothelial growth factor A (VEGF-A). TAMs accumulate in hypoxic regions of the tumor, which induces the expression of hypoxia-inducible factors (HIF-1) that regulate VEGF expression. In addition to producing VEGF-A, TAMs have been shown to modulate VEGF-A concentration through matrix metalloproteinase (MMP)-9 activity and by producing WNT7B that induces endothelial cells to produce VEGF-A.
In addition to VEGF-A, TAMs secrete the pro-angiogenic factors tumor necrosis factor α (TNFα), basic fibroblast growth factor, urokinase-type plasminogen activator, adrenomedullin, and semaphorin 4D. Moreover, cytokines produced by TAMs induce tumor cells to produce pro-angiogenic factors, thereby working cooperatively to turn on the angiogenic switch.
A class of TAMs expressing Tie2 have been shown to induce tumor angiogenesis. Tie2+ TAMs associate with blood vessels through angiopoietin-2 produced by endothelial cells and activate angiogenesis through paracrine signaling. When angiopoietin-2 is bound, these TAMs upregulate expression of more angiogenic factors, such as thymidine phosphorylase and cathepsin B. Angiopoietin-2 also causes Tie2+ TAMs to express T-cell regulating factors interleukin (IL)-10 and chemokine (C-C motif) ligand (CCL) 17; these factors limit T-cell proliferation and upregulate expansion of regulatory T cells, allowing tumor cells to evade immune responses. Moreover, tumor-produced colony stimulating factor-1 (CSF1), which regulates macrophage lineage, increases expression of Tie2 on TAMs, suggesting that CSF1 and Tie2+ TAMs may play a role in the angiogenic switch.
Tumor lymphangiogenesis is closely related to tumor angiogenesis, and there is substantial evidence that factors produced by TAMs, especially those of the VEGF family and their receptor tyrosine kinases, are responsible for this correlation, which could be in part causal. 
Suppressing the Immune System
One of the major functions of TAMs is suppressing the T-cell mediated anti-tumor immune response. Gene expression analysis of mouse models of breast cancer and fibrosarcoma shows that TAMs have immunosuppressive transcriptional profiles and express factors including IL-10 and transforming growth factor β (TGFβ). In humans, TAMs have been shown to directly suppress T cell function through surface presentation of programmed death-ligand 1 (PD-L1) in hepatocellular carcinomaand B7-homologs in ovarian carcinoma, which activate programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), respectively, on T cells. Inhibitory signals to PD-1 and CTLA-4 are immune checkpoints, and binding of these inhibitory receptors by their ligands prevents T cell receptor signaling, inhibits T cells cytotoxic function, and promotes T cell apoptosis. HIF-1α also induces TAMs to suppress T cell function through arginase-1, but the mechanism by which this occurs is not yet fully understood.
TAMs have historically been described as falling into two categories: M1 and M2. M1 refers to macrophages that undergo “classical” activation by interferon-γ (IFNγ) with either lipopolysaccharide (LPS) or TNF, whereas M2 refers to macrophages that undergo “alternative” activation by IL-4. M1 macrophages are seen to have a pro-inflammatory and cytotoxic (anti-tumoral) function; M2 macrophages are anti-inflammatory (pro-tumoral) and promote wound healing. However, use of the M1/M2 polarization paradigm has led to confusing terminology since M1/M2 are used to describe mature macrophages, but the activation process is complex and involves many related cells in the macrophage family. Moreover, with recent evidence that macrophage populations are tissue- and tumor-specific, it has been proposed that classifying macrophages, including TAMs, as being in one of two distinct stable subsets is insufficient. Rather, TAMs should be viewed as existing on a spectrum. More comprehensive classification systems that account for the dynamic nature of macrophages have been proposed, but have not been adopted by the immunological research community.
In many tumor types TAM infiltration level has been shown to be of significant prognostic value. TAMs have been linked to poor prognosis in breast cancer, ovarian cancer, types of glioma and lymphoma; better prognosis in colon and stomach cancers and both poor and better prognoses in lung and prostate cancers.
Clinically, in 128 patients with breast cancer it was found that patients with more M2 tumor-associated macrophages had higher-grade tumors, greater microvessel density, and worse overall survival. Patients with more M1 tumor-associated macrophages displayed the opposite effect.
CSF1R inhibitors have been developed as a potential route to reduce the presence of TAMs in the tumor microenvironment. As of 2017, CSF1R inhibitors that are currently in early stage clinical trials include Pexidartinib, PLX7486, ARRY-382, JNJ-40346527, BLZ945, Emactuzumab, AMG820, IMC-CS4, MCS110, and Cabiralizumab. CSF1R inhibitors such as PLX3397 have also been shown to alter the distribution of TAMs throughout the tumor and promote enrichment of the classically activated M1-like phenotype.
Other approaches to enhance tumor response to chemotherapies that have been tested in preclinical models include blocking macrophage recruitment to the tumor site, re-polarizing TAMs, and promoting TAM activation. Remaining challenges in targeting TAMs include determining whether to target depletion or repolarization in combination therapies, and for which tumor types and at what tumor stage TAM-targeted therapy is effective. Re-polarization of TAMs from a M2 to M1 phenotype by drug treatments has shown the ability to control tumor growth, including in combination with checkpoint inhibitor therapy.
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- Komohara, Yoshihiro; Fujiwara, Yukio; Ohnishi, Koji; Takeya, Motohiro (April 2016). “Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy”. Advanced Drug Delivery Reviews. 99 (Pt B): 180–185. doi:10.1016/j.addr.2015.11.009. PMID 26621196.
- Ostuni, Renato; Kratochvill, Franz; Murray, Peter J.; Natoli, Gioacchino (April 2015). “Macrophages and cancer: from mechanisms to therapeutic implications”. Trends in Immunology. 36 (4): 229–239. doi:10.1016/j.it.2015.02.004. PMID 25770924.
- Qian, Bin-Zhi; Pollard, Jeffrey W. (April 2010). “Macrophage Diversity Enhances Tumor Progression and Metastasis”. Cell. 141 (1): 39–51. doi:10.1016/j.cell.2010.03.014. PMC 4994190. PMID 20371344.
- Mantovani, Alberto; Marchesi, Federica; Malesci, Alberto; Laghi, Luigi; Allavena, Paola (24 January 2017). “Tumour-associated macrophages as treatment targets in oncology”. Nature Reviews Clinical Oncology. 14 (7): 399–416. doi:10.1038/nrclinonc.2016.217. PMC 5480600. PMID 28117416.
- Riabov, Vladimir; Gudima, Alexandru; Wang, Nan; Mickley, Amanda; Orekhov, Alexander; Kzhyshkowska, Julia (5 March 2014). “Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis”. Frontiers in Physiology. 5: 75. doi:10.3389/fphys.2014.00075. PMC 3942647. PMID 24634660.
- Bergers, Gabriele; Brekken, Rolf; McMahon, Gerald; Vu, Thiennu H.; Itoh, Takeshi; Tamaki, Kazuhiko; Tanzawa, Kazuhiko; Thorpe, Philip; Itohara, Shigeyoshi; Werb, Zena; Hanahan, Douglas (1 October 2000). “Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis”. Nature Cell Biology. 2 (10): 737–744. doi:10.1038/35036374. PMC 2852586. PMID 11025665.
- Yeo, E.-J.; Cassetta, L.; Qian, B.-Z.; Lewkowich, I.; Li, J.-f.; Stefater, J. A.; Smith, A. N.; Wiechmann, L. S.; Wang, Y.; Pollard, J. W.; Lang, R. A. (17 March 2014). “Myeloid WNT7b Mediates the Angiogenic Switch and Metastasis in Breast Cancer”. Cancer Research. 74 (11): 2962–2973. doi:10.1158/0008-5472.CAN-13-2421. PMC 4137408. PMID 24638982.
- De Palma, Michele; Venneri, Mary Anna; Galli, Rossella; Sergi, Lucia Sergi; Politi, Letterio S.; Sampaolesi, Maurilio; Naldini, Luigi (September 2005). “Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors”. Cancer Cell. 8 (3): 211–226. doi:10.1016/j.ccr.2005.08.002. PMID 16169466.
- Coffelt, Seth B.; Chen, Yung-Yi; Muthana, Munitta; Welford, Abigail F.; Tal, Andrea O.; Scholz, Alexander; Plate, Karl H.; Reiss, Yvonne; Murdoch, Craig; De Palma, Michele; Lewis, Claire E. (1 April 2011). “Angiopoietin 2 Stimulates TIE2-Expressing Monocytes To Suppress T Cell Activation and To Promote Regulatory T Cell Expansion”. The Journal of Immunology. 186 (7): 4183–4190. doi:10.4049/jimmunol.1002802. PMID 21368233.
- Forget, Mary A.; Voorhees, Jeffrey L.; Cole, Sara L.; Dakhlallah, Duaa; Patterson, Ivory L.; Gross, Amy C.; Moldovan, Leni; Mo, Xiaokui; Evans, Randall; Marsh, Clay B.; Eubank, Tim D.; Valledor, Annabel (3 June 2014). “Macrophage Colony-Stimulating Factor Augments Tie2-Expressing Monocyte Differentiation, Angiogenic Function, and Recruitment in a Mouse Model of Breast Cancer”. PLoS ONE. 9(6): e98623. doi:10.1371/journal.pone.0098623. PMC 4043882. PMID 24892425.
- Gomes, Fausto Gueths; Nedel, Fernanda; Alves, Alessandro Menna; Nör, Jacques Eduardo; Tarquinio, Sandra Beatriz Chaves (February 2013). “Tumor angiogenesis and lymphangiogenesis: Tumor/endothelial crosstalk and cellular/microenvironmental signaling mechanisms”. Life Sciences. 92 (2): 101–107. doi:10.1016/j.lfs.2012.10.008. PMC 3740377. PMID 23178150.
- Scavelli, C; Vacca, A; Di Pietro, G; Dammacco, F; Ribatti, D (1 April 2004). “Crosstalk between angiogenesis and lymphangiogenesis in tumor progression”. Leukemia. 18 (6): 1054–1058. doi:10.1038/sj.leu.2403355. PMID 15057248.
- Biswas, S. K. (1 March 2006). “A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF- B and enhanced IRF-3/STAT1 activation)”. Blood. 107 (5): 2112–2122. doi:10.1182/blood-2005-01-0428. PMID 16269622.
- Ojalvo, Laureen S.; King, William; Cox, Dianne; Pollard, Jeffrey W. (March 2009). “High-Density Gene Expression Analysis of Tumor-Associated Macrophages from Mouse Mammary Tumors”. The American Journal of Pathology. 174 (3): 1048–1064. doi:10.2353/ajpath.2009.080676. PMC 2665764. PMID 19218341.
- Kuang, Dong-Ming; Zhao, Qiyi; Peng, Chen; Xu, Jing; Zhang, Jing-Ping; Wu, Changyou; Zheng, Limin (8 June 2009). “Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1″. The Journal of Experimental Medicine. 206 (6): 1327–1337. doi:10.1084/jem.20082173. PMC 2715058. PMID 19451266.
- Kryczek, Ilona; Zou, Linhua; Rodriguez, Paulo; Zhu, Gefeng; Wei, Shuang; Mottram, Peter; Brumlik, Michael; Cheng, Pui; Curiel, Tyler; Myers, Leann; Lackner, Andrew; Alvarez, Xavier; Ochoa, Augusto; Chen, Lieping; Zou, Weiping (17 April 2006). “B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma”. The Journal of Experimental Medicine. 203 (4): 871–881. doi:10.1084/jem.20050930. PMC 2118300. PMID 16606666.
- Noy, Roy; Pollard, Jeffrey W. (July 2014). “Tumor-Associated Macrophages: From Mechanisms to Therapy”. Immunity. 41 (1): 49–61. doi:10.1016/j.immuni.2014.06.010. PMC 4137410. PMID 25035953.
- Doedens, A. L.; Stockmann, C.; Rubinstein, M. P.; Liao, D.; Zhang, N.; DeNardo, D. G.; Coussens, L. M.; Karin, M.; Goldrath, A. W.; Johnson, R. S. (14 September 2010). “Macrophage Expression of Hypoxia-Inducible Factor-1 Suppresses T-Cell Function and Promotes Tumor Progression”. Cancer Research. 70 (19): 7465–7475. doi:10.1158/0008-5472.CAN-10-1439. PMC 2948598. PMID 20841473.
- Martinez, Fernando O.; Gordon, Siamon (3 March 2014). “The M1 and M2 paradigm of macrophage activation: time for reassessment”. F1000Prime Reports. 6: 13. doi:10.12703/P6-13. PMC 3944738. PMID 24669294.
- Allavena, P.; Sica, A.; Solinas, G.; Porta, C.; Mantovani, A. (2008). “The inflammatory micro-environment in tumor progression: The role of tumor-associated macrophages”. Critical Reviews in Oncology/Hematology. 66 (1): 1–9. doi:10.1016/j.critrevonc.2007.07.004. PMID 17913510.
- De la Cruz-Merino L, Barco-Sanchez A, Henao Carrasco F, et al.: New insights into the role of the immune microenvironment in breast carcinoma. Dev Immunol 2013; 2013: 785317.
- Williams, Carly Bess; Yeh, Elizabeth S; Soloff, Adam C (2016-01-20). “Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy”. Npj Breast Cancer. 2 (1). doi:10.1038/npjbcancer.2015.25. ISSN 2374-4677. PMC 4794275. PMID 26998515.
- Pyonteck, Stephanie M.; Akkari, Leila; Schuhmacher, Alberto J.; Bowman, Robert L.; Sevenich, Lisa; Quail, Daniela F.; Olson, Oakley C.; Quick, Marsha L.; Huse, Jason T.; Teijeiro, Virginia; Setty, Manu; Leslie, Christina S.; Oei, Yoko; Pedraza, Alicia; Zhang, Jianan; Brennan, Cameron W.; Sutton, James C.; Holland, Eric C.; Daniel, Dylan; Joyce, Johanna A. (October 2013). “CSF-1R inhibition alters macrophage polarization and blocks glioma progression”. Nature Medicine. 19(10): 1264–1272. doi:10.1038/nm.3337. ISSN 1078-8956. PMC 3840724. PMID 24056773.
- Cannarile; et al. (2017). “Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy”. Journal for ImmunoTherapy of Cancer. 5 (1): 53. doi:10.1186/s40425-017-0257-y. PMC 5514481. PMID 28716061.
- Sankhala, Kamalesh Kumar; Blay, Jean-Yves; Ganjoo, Kristen N.; Italiano, Antoine; Hassan, Andrew Bassim; Kim, Tae Min; Ravi, Vinod; Cassier, Philippe Alexandre; Rutkowski, Piotr; Sankar, Neil; Qazi, Ibrahim; Sikorski, Robert S.; Collins, Helen; Zhang, Charlie; Shocron, Ellyn; Gelderblom, Hans (2017). “A phase I/II dose escalation and expansion study of cabiralizumab (cabira; FPA-008), an anti-CSF1R antibody, in tenosynovial giant cell tumor (TGCT, diffuse pigmented villonodular synovitis D-PVNS)”. Journal of Clinical Oncology. 35 (15_suppl): 11078. doi:10.1200/JCO.2017.35.15_suppl.11078.
- A Study to of Cabiralzumab Given by Itself or With Nivolumab in Advanced Cancer or Cancer That Has Spread
- Novel Combination Shows Promising Responses in Pancreatic Cancer Nov 2017
- Cuccarese, Michael F.; Dubach, J. Matthew; Pfirschke, Christina; Engblom, Camilla; Garris, Christopher; Miller, Miles A.; Pittet, Mikael J.; Weissleder, Ralph (2017-02-08). “Heterogeneity of macrophage infiltration and therapeutic response in lung carcinoma revealed by 3D organ imaging”. Nature Communications. 8: 14293. doi:10.1038/ncomms14293. ISSN 2041-1723. PMC 5309815. PMID 28176769.
- Rodell, Christopher B.; Arlauckas, Sean P.; Cuccarese, Michael F.; Garris, Christopher S.; Li, Ran; Ahmed, Maaz S.; Kohler, Rainer H.; Pittet, Mikael J.; Weissleder, Ralph (2018-05-21). “TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy”. Nature Biomedical Engineering. 2 (8): 578–588. doi:10.1038/s41551-018-0236-8. ISSN 2157-846X.
- Ruffell, Brian; Coussens, Lisa M. (April 2015). “Macrophages and Therapeutic Resistance in Cancer”. Cancer Cell. 27 (4): 462–472. doi:10.1016/j.ccell.2015.02.015. PMC 4400235. PMID 25858805.
- Guerriero, Jennifer L.; Sotayo, Alaba; Ponichtera, Holly E.; Castrillon, Jessica A.; Pourzia, Alexandra L.; Schad, Sara; Johnson, Shawn F.; Carrasco, Ruben D.; Lazo, Suzan (March 2017). “Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages”. Nature. 543 (7645): 428–432. doi:10.1038/nature21409. ISSN 0028-0836. PMID 28273064.