Tumor Hypoxia Does Not Drive Differentiation of Tumor-Associated Macrophages but Rather Fine-Tunes the M2-like Macrophage Population

Laoui, Damya; Overmeire, Eva Van; Conza, Giusy Di; Aldeni, Chiara; Keirsse, Jiri; Morias, Yannick; Movahedi, Kiavash; Houbracken, Isabelle; Schouppe, Elio; Elkrim, Yvon; Karroum, Oussama; Jordan, Bénédicte F.; Carmeliet, Peter; Gysemans, Conny; Baetseĺier, Patrick De; Mazzone, Massimiliano; Ginderachter, Jo A. Van

doi:10.1158/0008-5472.can-13-1196

Cited by 360 publications

(309 citation statements)

References 20 publications

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“…TAMs with low MHC-II expression (MHC-II lo ) populate hypoxic areas, whereas TAMs with high MHC-II expression (MHC-II hi ) populate normoxic areas. While hypoxia does not seem to influence differentiation of these two TAM subsets or MHC-II expression levels, hypoxia does influence the MHC-II lo macrophage phenotype by fine-tuning hypoxia-responsive genes that are involved in metabolism, angiogenesis, and metastasis, thereby fostering tumor progression (74). The underlying mechanism for this phenotypic switch in MHC-II lo compared to MHC-II hi macrophages, as well as why MHC-II lo macrophages specifically reside in hypoxic areas, remains an open question; nevertheless, the gene expression profile specifically affected in these macrophages by hypoxia, such as increased availability of VEGFA, lactate dehydrogenase A (LDHA), or urokinase-type plasminogen activator receptor (uPAR) underscores the contribution of MHC-II lo macrophages to tumor progression.…”

Section: Cd25mentioning

confidence: 93%

The impact of hypoxia on tumor-associated macrophages

Henze¹,

Mazzone²

2016

Journal of Clinical Investigation

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347

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Section: Cd25mentioning

confidence: 93%

The impact of hypoxia on tumor-associated macrophages

Henze¹,

Mazzone²

2016

Journal of Clinical Investigation

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452

347

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“…Tumor promotion has been linked with an accumulation of M2-oriented MHC II low TAMs in lung and breast carcinoma (3,4). Accordingly, MHC II low TAMs were found to reside primarily in less oxygenated zones, express hypoxia-regulated genes, and facilitate the angiogenic switch (5). Interestingly, the macrophage mannose receptor (MMR, CD206), a typical M2 cell surface marker, is upregulated on these tumor-promoting MHC II low TAMs in all tumor models studied (3)(4)(5).…”

mentioning

confidence: 99%

“…Accordingly, MHC II low TAMs were found to reside primarily in less oxygenated zones, express hypoxia-regulated genes, and facilitate the angiogenic switch (5). Interestingly, the macrophage mannose receptor (MMR, CD206), a typical M2 cell surface marker, is upregulated on these tumor-promoting MHC II low TAMs in all tumor models studied (3)(4)(5). The M1/M2 nomenclature has shortcomings, and a better positioning of TAM subsets within the spectrum of macrophage activation states is warranted (6).…”

mentioning

confidence: 99%

PET Imaging of Macrophage Mannose Receptor–Expressing Macrophages in Tumor Stroma Using ¹⁸F-Radiolabeled Camelid Single-Domain Antibody Fragments

et al. 2015

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Tumor-associated macrophages constitute a major component of the stroma of solid tumors, encompassing distinct subpopulations with different characteristics and functions. We aimed to identify M2-oriented tumor-supporting macrophages within the tumor microenvironment as indicators of cancer progression and prognosis, using PET imaging. This can be realized by designing 18 F-labeled camelid single-domain antibody fragments (sdAbs) specifically targeting the macrophage mannose receptor (MMR), which has been identified as an important biomarker on this cell population. Methods: Crossreactive anti-MMR sdAbs were generated after immunization of an alpaca with the extracellular domains of both human and mouse MMR. The lead binder was chosen on the basis of comparisons of binding affinity and in vivo pharmacokinetics. The PET tracer 18 F-fluorobenzoate (FB)-anti-MMR sdAb was developed using the prosthetic group N-succinimidyl-4-18 F-fluorobenzoate ( 18 F-SFB), and its biodistribution, tumor-targeting potential, and specificity in terms of macrophage and MMR targeting were evaluated in mouse tumor models. Results: Four sdAbs were selected after affinity screening, but only 2 were found to be cross-reactive for human and mouse MMR. The lead anti-MMR 3.49 sdAb, bearing an affinity of 12 and 1.8 nM for mouse and human MMR, respectively, was chosen for its favorable in vivo biodistribution profile and tumor-targeting capacity. 18 F-FB-anti-MMR 3.49 sdAb was synthesized with a 5%-10% radiochemical yield using an automated and optimized protocol. In vivo biodistribution analyses showed fast clearance via the kidneys and retention in MMRexpressing organs and tumor. The kidney retention of the fluorinated sdAb was 20-fold lower than a 99m Tc-labeled counterpart. Compared with MMR-and C-C chemokine receptor 2-deficient mice, significantly higher uptake was observed in tumors grown in wild-type mice, demonstrating the specificity of the 18 F tracer for MMR and macrophages, respectively. Conclusion: Anti-MMR 3.49 was denoted as the lead cross-reactive MMR-targeting sdAb. 18 F radiosynthesis was optimized, providing an optimal probe for PET imaging of the tumor-promoting macrophage subpopulation in the tumor stroma. Dur ing tumor development, myeloid cells are attracted to the tumor stroma. These infiltrating immune cells are versatile, adopting different activation states in response to a changing microenvironment, leading to subsets of tumor-associated macrophages (TAMs) with specialized functions (1,2). Two main morphologically distinct TAM subsets can be distinguished on the basis of major histocompatibility complex (MHC) class II expression levels in multiple mouse tumor models. Tumor promotion has been linked with an accumulation of M2-oriented MHC II low TAMs in lung and breast carcinoma (3,4). Accordingly, MHC II low TAMs were found to reside primarily in less oxygenated zones, express hypoxia-regulated genes, and facilitate the angiogenic switch (5). Interestingly, the macrophage mannose receptor (MMR, CD206), a typical M2...

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“…More work is needed to elucidate the mechanisms by which hypoxia and immune cells establish microenvironments leading to intratumoral heterogeneity. Enhanced imaging techniques have made it clear that distinct subpopulations of hypoxic cells are present in tumors (125)(126)(127), while histopathological and molecular analyses have shown that distinct tumor regions have different inflammatory infiltrates that can be modulated by intratumoral hypoxia (128,129).…”

Section: Hypoxia and Intratumoral Heterogeneitymentioning

confidence: 99%