The Cellular and Molecular Origin of Tumor-associated Macrophages

By R. A. Franklin, W. Liao, A. Sarkar, Myoungjoo V. Kim, Michael Bivona, Kang Liu, Eric G. Pamer, Ming O. Li. Science, 2014

1,252 citations recorded by the source corpus.

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases, including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an “alternatively activated” phenotype. TAM terminal differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy. Origins of tumor macrophages To help the immune system fight cancer, it is important to understand the origins and functions of immune cells in tumors and the surrounding tissues. One type of immune cells, macrophages, is present both in tumors and in nearby noncancerous tissue, but the relationship between these two cell populations is unclear. Franklin et al. found that tumor-associated macrophages in mouse mammaries differed in form, function, and origin from macrophages found in nearby noncancerous mammary tissue. Moreover, when they removed macrophages from the tumors but not the other mammary tissue, tumors shrank and cytotoxic T cells—another kind of immune cell that kills tumor cells—infiltrated the tumors. Tumor-associated macrophages may thus be an important therapeutic target. Science, this issue p. 921. The origins of tumor-associated macrophages in a mouse mammary tumor model are revealed. [Also see Perspective by Perdiguero and Geissmann]

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/2440e401e091e113b21cf94f05618daa61ff2325

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. A. Mantovani
2. Lisa M. Coussens
3. P. Allavena
4. J. Pollard
5. R. Noy
6. A. Sica
7. M. Locati
8. Jong-Sup Bae

In Oncology

1. A. Mantovani
2. P. Allavena
3. J. Pollard
4. Lisa M. Coussens
5. R. Noy
6. M. Locati
7. L. Chávez-Galán
8. I. Garcia

Citations in the corpus

• Tumor-associated macrophages: from mechanisms to therapy (2014, background): “Nevertheless, several recent studies suggest that most TAM subpopulations arise from the Ly6C+ population of circulating mouse monocytes in grafted tumors (Movahedi et al., 2010), primary mouse mammary tumors (Franklin et al., 2014), and in lung metastases (Qian et al., 2011).”
• Tumor-associated macrophages: from basic research to clinical application (2017, background): “In a polyoma middle T oncoprotein model, the binding of chemokine (C-C motif ) ligand (CCL) 2 to chemokine (C-C motif ) receptor (CCR) 2 directly mediated monocyte recruitment to the primary tumor and metastases [9].”
• Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets (2019, background): “(legend continued on next page) Cancer Cell 35, 588–602, April 15, 2019 589 origins; however, in most cancer models, TAMs are recruited from bone marrow progenitors known as monocytes (Arwert et al., 2018; Franklin et al., 2014; Qian et al., 2011).”
• The nature of myeloid-derived suppressor cells in the tumor microenvironment (2016, background): “TAM are phenotypically closer to the M2 end of the functional spectrum, although there is evidence indicating that they can display features of M1-like cells [72,86,87].”
• Progress in tumor-associated macrophage (TAM)-targeted therapeutics (2017, neutral): “1 Inhibition of CCR2-CCL2 signaling—The number of intratumoral TAMs increases with tumor growth due to self-proliferation as well as recruitment and differentiation from circulating inflammatory Ly6C+CCR2+ monocytes [104].”
• Tumor-Associated Macrophages in Tumor Immunity (2020, background): “Tumor growth can also induce the differentiation of CCR2+ monocytes into TAMs (10).”
• Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment (2016, background): “Though we have evidence that both tissue-resident and recruited macrophages may coexist in tumors, that TAMs in a murine mammary tumor model are phenotypically and functionally distinct from mammary tissue-resident macrophages, and also that recruited macrophages may differentiate and form the major”