Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

Lahmar, Qods; Keirsse, Jiri; Laoui, Damya; Movahedi, Kiavash; Overmeire, Eva Van; Ginderachter, Jo A. Van

doi:10.1016/j.bbcan.2015.06.009

Cited by 108 publications

(120 citation statements)

References 189 publications

(218 reference statements)

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“…These include suppression of anti-tumor cytotoxic T cells, promotion of tumor cell growth, motility, invasion, intravasation, angiogenesis, and ECM deposition (Afik et al, 2016; Gocheva et al, 2010; Hughes et al, 2015; Lahmar et al, 2016; Lewis et al, 2016; Noy and Pollard, 2014; De Palma et al, 2005). Many of these functions are ascribed to the M2-polarization of TAMs, and therapeutic approaches aimed at driving TAMs toward M1-polarization have shown promise in mouse models of cancer (Georgoudaki et al, 2016; Pyonteck et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake

et al. 2017

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Summary Physiologic turnover of interstitial collagen is mediated by a sequential pathway, in which collagen is fragmented by pericellular collagenases, endocytosed by collagen receptors, and routed to lysosomes for degradation by cathepsins. Here, we used intravital microscopy to investigate if malignant tumors, which are characterized by high rates of extracellular matrix turnover, utilize a similar collagen degradation pathway. Tumors of epithelial, mesenchymal, or neural crest origin all displayed vigorous endocytic collagen degradation. The cells engaged in this process were identified as tumor-associated macrophage (TAM)-like cells that degraded collagen in a mannose receptor-dependent manner. Accordingly, mannose receptor-deficient mice displayed increased intra-tumoral collagen. Whole transcriptome profiling uncovered a distinct extracellular matrix-catabolic signature of these collagen-degrading TAMs. Lineage-ablation studies revealed that collagen-degrading TAMs originated from circulating CCR2+ monocytes. The study identifies a function of TAMs in altering the tumor microenvironment through endocytic collagen turnover and establishes macrophages as centrally engaged in tumor-associated collagen degradation.

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Section: Discussionmentioning

confidence: 99%

“…TAMs derive from tissue-resident macrophages or from recruited inflammatory monocytes conditioned by the tumor microenvironment (Franklin et al, 2014; Lahmar et al, 2016; Noy and Pollard, 2014), and the density of TAMs correlates with prognosis (Biswas et al, 2013; Zhang et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake

et al. 2017

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“…The tumor associated macrophage (TAM) is a particularly enigmatic participant in this microenvironment. TAMs may be recruited from nearby tissue resident macrophages or from monocytes in circulation [4,5]. Due to macrophage plasticity, TAMs exist as a heterogeneous population and may be broadly categorized as classically activated M1 or alternatively activated M2 macrophages [6].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of multivalent M2pep peptides for targeting alternatively activated M2 macrophages

Ngambenjawong

Cieslewicz

Schellinger

et al. 2016

Journal of Controlled Release

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The tumor microenvironment in the majority of cancers is known to favor polarization of tumor-associated macrophages (TAMs) to alternatively activated M2 phenotype, promoting disease progression and reducing patient survival. Effective therapy targeting this M2 macrophage population is thus a promising adjuvant to approved cancer therapies. One of the challenges in targeting M2-like TAMs is a lack of high affinity targeting ligand with good selectivity over anti-tumor M1-like TAMs. We have previously identified an M2 macrophage-targeting peptide (M2pep) that binds preferentially to murine M2 macrophages and M2-like TAMs. A fusion peptide of M2pep with pro-apoptotic peptide KLA (M2pepKLA) was further used to reduce TAM population in vivo but high concentrations and frequent dosing were required due to low binding affinity of M2pep for M2 macrophage. The goal of this study was to develop more potent TAM depletion constructs by increasing the valency of both the M2pep targeting and KLA drug domains. Divalent and tetravalent displays of M2pep ([M2pep]2-Biotin and [M2pep]4-Biotin) were synthesized and evaluated for improvement in binding avidity to the murine macrophages. High avidity and selective binding of [M2pep]2-Biotin to M2 macrophages was achieved with at least 10-fold lower concentration than required for monovalent M2pep activity. Increasing M2pep valency to four, however, resulted in a reduction in both binding activity and selectivity. Surprisingly, both divalent and tetravalent M2pep, without conjugation of any cytotoxic drug cargo, exhibited M2 macrophage-selective toxicity not observed in monovalent M2pep treatment. We next synthesized divalent M2pep with monovalent and divalent KLA ([M2pep]2-[KLA] and [M2pep]2-[KLA]2) to evaluate its enhanced potency compared to M2pepKLA. While both constructs were significantly more toxic than M2pepKLA to primary, bone marrow-derived M2 macrophage, desired selectivity was retained only with [M2pep]2-[KLA]. Finally, we evaluated all multivalent M2pep and M2pepKLA analogs using a syngeneic CT-26 tumor cell suspension. In this setting, [M2pep]4-Biotin and [M2pep]2-[KLA]2 exhibited selective toxicity to both M2-like TAMs and malignant cells but not to M1-like TAMs. Therefore, these constructs are promising anti-cancer constructs with dual-modality mechanisms: malignant cell killing and TAM-based immunomodulation.

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“…Although high numbers of TAMs correlate with poor prognosis in many cancers, 3,4 colorectal cancer is one of the few exceptions to this association. 50 Many studies reported that a high density of CD68 + TAMs at the invasive front was related to a favorable prognosis of patients with colorectal cancer.…”

Section: Colorectal Cancermentioning

confidence: 99%

Role of tumor‐associated macrophages in human malignancies: friend or foe?

Takeya

Komohara

2016

Pathology International

150

154

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Tumor-associated macrophages (TAMs) play a pivotal role in tumor growth in human malignancies. Published studies have analyzed the relationship between TAM infiltration and the prognosis of patients for many human tumors. Most studies reported a positive correlation between TAM density and a poor prognosis. Studies focusing on macrophage phenotypes emphasized the protumor role of M2 anti-inflammatory macrophages in many types of human tumors. However, TAMs influence tumor progression in various ways that depend on differences in tumor sites, histology, and microenvironments. In this review, we summarize the function of TAMs in various human malignancies by reviewing the data provided in studies of TAMs in human malignancies.

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Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment

Cited by 108 publications

References 189 publications

Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake

Tumor-Associated Macrophages Derived from Circulating Inflammatory Monocytes Degrade Collagen through Cellular Uptake

Synthesis and evaluation of multivalent M2pep peptides for targeting alternatively activated M2 macrophages

Role of tumor‐associated macrophages in human malignancies: friend or foe?

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