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Review
. 2015 Apr 13;27(4):462-72.
doi: 10.1016/j.ccell.2015.02.015. Epub 2015 Apr 6.

Macrophages and therapeutic resistance in cancer

Affiliations
Review

Macrophages and therapeutic resistance in cancer

Brian Ruffell et al. Cancer Cell. .

Abstract

How neoplastic cells respond to therapy is not solely dependent on the complexity of the genomic aberrations they harbor but is also regulated by numerous dynamic properties of the tumor microenvironment. Identifying and targeting critical pathways that improve therapeutic efficacy by bolstering anti-tumor immune responses holds great potential for improving outcomes and impacting long-term patient survival. Macrophages are key regulators of homeostatic tissue and tumor microenvironments. Therefore, therapeutics impacting macrophage presence and/or bioactivity have shown promise in preclinical models and are now being evaluated in the clinic. This review discusses the molecular/cellular pathways identified so far whereby macrophages mediate therapeutic responses.

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Figures

Figure 1
Figure 1. Clinical implications of macrophage density
Organs where tumor progression and/or clinical outcome are negatively associated with increased macrophage density are shown in red. Green indicates a positive association. Organs where the implications of macrophages density are unclear or unknown are shown in gray and black, respectively. Image created by Tarot Walker.
Figure 2
Figure 2. Macrophage polarization as a dynamic system
The integration of multiple signals emanating from the tumor microenvironment (outer circle) dictates the functional role of macrophages (inner circle). Integrins and toll-like receptors (TLRs) will be engaged by multiple ligands.
Figure 3
Figure 3. Macrophage function in the tumor microenvironment
(a) Macrophage expression of IL-6 and TNF-α promotes survival signaling in neoplastic cells and resistance to chemotherapy and targeted agents. Expression of survival factors is dependent upon the protease activity of cathepsin B and/or S. (b) Neoplastic cell invasion of ectopic tissue can be promoted through directed release of cytokines/chemokines such as EGF and CCL18, or through protease-dependent ECM remodeling that may directly affect neoplastic migration or increase chemoattractant bioavailability. EGF expression is driven by signaling through the CSF-1R via neoplastic cell production of CSF-1, as well as T cell-derived IL-4 (not shown). (c) Macrophages directly promote angiogenesis via production of VEGFA and other angiogenic factors, and can enhance VEGFA expression by endothelial cells through WNT7B. A subset of macrophages expressing the Tie2 receptor are recruited to the vasculature by mural cell/pericyte expression of ANG2 and are important in regulating vascular structure. (d) Direct suppression of a cytotoxic T cell (CTL) response can occur via expression of B7 family ligands (PD-L1, B7-H4). Indirect suppression may occur through release of IL-10 or recruitment of IL-10-expressing regulatory T cells (TReg) via CCL22, whereby IL-10 suppresses the capacity of dendritic cells to produce IL-12 and promote a TH1/CTL anti-tumor immune response.

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