Trends in Immunology
Volume 33, Issue 3, March 2012, Pages 119-126
Journal home page for Trends in Immunology

Review
Differential macrophage programming in the tumor microenvironment

https://doi.org/10.1016/j.it.2011.12.001Get rights and content

Of the multiple unique stromal cell types common to solid tumors, tumor-associated macrophages (TAMs) are significant for fostering tumor progression. The protumor properties of TAMs derive from regulation of angiogenic programming, production of soluble mediators that support proliferation, survival and invasion of malignant cells, and direct and indirect suppression of cytotoxic T cell activity. These varied activities are dependent on the polarization state of TAMs that is regulated in part by local concentrations of cytokines and chemokines, as well as varied interactions of TAMs with normal and degraded components of the extracellular matrix. Targeting molecular pathways regulating TAM polarization holds great promise for anticancer therapy.

Section snippets

Macrophages in solid malignancies

Macrophages are important residents of all tissues, where they play crucial roles in regulating tissue homeostasis. In this context, tissue-resident macrophages assist with combating infection 1, 2, resolving acute inflammation [3], and in regulating metabolic response to tissue stress 4, 5. This broad range of functions, and the accompanying plasticity required to permit such adaptive responses, also implicates macrophages in several chronic pathological conditions including diabetes and

TAM function

With the exception of non-small cell lung carcinoma 12, 13, patient prognosis in solid tumors is generally described as correlating inversely with TAM density and expression signatures 10, 14. TAMs have also been related to particular functional roles in human tumors, with an established association between TAM presence and density of tumor vasculature in several carcinomas 15, 16, 17, 18 including breast 19, 20, 21, 22, 23, 24, as well as increased local invasion and/or metastasis in melanoma

Mechanisms of TAM polarization

The description of macrophage activation as either classical [M1; interferon (IFN)γ/lipopolysaccharide (LPS)-dependent] or alternative (M2; IL-4/IL-13/IL-10/FcγR-dependent) has provided a necessary framework for the understanding of TAM polarization [88]. However, even though the M1/M2 designations represent extreme ends of a scale, the concept is an oversimplification of the diversity of TAM phenotypes evident simply based on their localization within tumors (Figure 1). TAMs do not become

Concluding remarks: targets for therapy

The pathways that engage and mediate the maladaptive response of TAMs present attractive therapeutic targets; several of which have already shown promise in the preclinical arena, and improve therapeutic responses to chemotherapy 37, 50, 120. Therapeutic strategies directed at TAMs can be grouped crudely into four prospective themes: blocking effector function, limiting recruitment, reprogramming, or preventing protumor polarization. Monoclonal antibodies and small molecular inhibitors

Acknowledgments

The authors thank Dr Anna Wasiuk for helpful discussion. This work was supported by a Department of Defense Breast Cancer Research Program (BCRP) Fellowship to B.R., and grants from the NIH/NCI (R01CA130980, R01CA132566, R01CA140943, R01 CA155331), the Department of Defense BCRP Era of Hope Scholar Expansion Award (W81XWH-10-BCRP-EOHS-EXP) and W81XWH-08-PRMRP-IIRA to L.M.C.

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    Current address: Department of Cell and Developmental Biology, Knight Cancer Institute, Oregon Health and Sciences University, Rm 5508, Richard Jones Hall, 3181 SW Sam Jackson Rd, Portland OR 97239-3098, USA.

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