Publications by authors named "Damya Laoui"

48 Publications

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Leuven, Belgium.

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.
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http://dx.doi.org/10.1126/sciadv.abf0466DOI Listing
May 2021

Therapeutic depletion of CCR8 tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy.

J Immunother Cancer 2021 Feb;9(2)

Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium

Background: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker.

Methods: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models.

Results: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of in conjunction with Treg activation markers. is also expressed by dysfunctional CD4 and CD8 T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs.

Conclusions: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy.
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http://dx.doi.org/10.1136/jitc-2020-001749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887378PMC
February 2021

Monocytic myeloid-derived suppressor cells home to tumor-draining lymph nodes via CCR2 and locally modulate the immune response.

Cell Immunol 2021 Apr 30;362:104296. Epub 2021 Jan 30.

Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address:

Efficient priming of anti-tumor T cells requires the uptake and presentation of tumor antigens by immunogenic dendritic cells (DCs) and occurs mainly in lymph nodes draining the tumor (tdLNs). However, tumors expand and activate myeloid-derived suppressor cells (MDSCs) that inhibit CTL functions by several mechanisms. While the immune-suppressive nature of the tumor microenvironment is largely documented, it is not known whether similar immune-suppressive mechanisms operate in the tdLNs. In this study, we analyzed MDSC characteristics within tdLNs. We show that, in a metastasis-free context, MO-MDSCs are the dominant MDSC population within tdLNs, that they are highly suppressive and that tumor proximity enhances their recruitment to tdLN via a CCR2/CCL2-dependent pathway. Altogether our results uncover a mechanism by which tumors evade the immune system that involves MDSC-mediated recruitment to the tdLN and the inhibition of T-cell activation even before reaching the highly immunosuppressive tumor microenvironment.
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http://dx.doi.org/10.1016/j.cellimm.2021.104296DOI Listing
April 2021

IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D.

Cancer Immunol Res 2021 Mar 23;9(3):309-323. Epub 2020 Dec 23.

Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.

IL1β is a central mediator of inflammation. Secretion of IL1β typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1β in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1β in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain-like protein in the host were dispensable for the release of intratumoral bioactive IL1β. Inflammasome-independent IL1β release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1β was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1β allowed intratumoral accumulation of CD8 effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8 T cells or macrophages abolished tumor growth inhibition in IL1β-deficient mice, demonstrating a crucial role for CD8 T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1β through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0431DOI Listing
March 2021

Targeting Neuropilin-1 with Nanobodies Reduces Colorectal Carcinoma Development.

Cancers (Basel) 2020 Nov 30;12(12). Epub 2020 Nov 30.

Laboratory for Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1040 Brussels, Belgium.

Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-II/trophic MHC-II macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was corroborated by an increase in the expression of genes associated with MHC-II macrophages and a decrease in the expression of MHC-II macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8 T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity.
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http://dx.doi.org/10.3390/cancers12123582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760077PMC
November 2020

Systemic Reprogramming of Monocytes in Cancer.

Front Oncol 2020 17;10:1399. Epub 2020 Sep 17.

Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.

Monocytes influence multiple aspects of tumor progression, including antitumor immunity, angiogenesis, and metastasis, primarily by infiltrating tumors, and differentiating into tumor-associated macrophages. Emerging evidence suggests that the tumor-induced systemic environment influences the development and phenotype of monocytes before their arrival to the tumor site. As a result, circulating monocytes show functional alterations in cancer, such as the acquisition of immunosuppressive activity and reduced responsiveness to inflammatory stimuli. In this review, we summarize available evidence about cancer-induced changes in monopoiesis and its impact on the abundance and function of monocytes in the periphery. In addition, we describe the phenotypical alterations observed in tumor-educated peripheral blood monocytes and highlight crucial gaps in our knowledge about additional cellular functions that may be affected based on transcriptomic studies. We also highlight emerging therapeutic strategies that aim to reverse cancer-induced changes in monopoiesis and peripheral monocytes to inhibit tumor progression and improve therapy responses. Overall, we suggest that an in-depth understanding of systemic monocyte reprogramming will have implications for cancer immunotherapy and the development of clinical biomarkers.
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http://dx.doi.org/10.3389/fonc.2020.01399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528630PMC
September 2020

A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling.

Cell Res 2020 09 19;30(9):745-762. Epub 2020 Jun 19.

VIB Center for Cancer Biology, Leuven, Belgium.

The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumor-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumors treated with checkpoint immunotherapy and identifying a naïve CD4 T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate the first panoramic view on the shared complexity of stromal cells in different cancers.
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http://dx.doi.org/10.1038/s41422-020-0355-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608385PMC
September 2020

IFNγ signaling response in peripheral blood monocytes: A new prognostic biomarker for breast cancer?

EBioMedicine 2020 03 25;53:102690. Epub 2020 Feb 25.

Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2020.102690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044706PMC
March 2020

Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer.

Cancers (Basel) 2019 Aug 27;11(9). Epub 2019 Aug 27.

Departments of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA-oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.
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http://dx.doi.org/10.3390/cancers11091255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769524PMC
August 2019

Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition.

J Immunother Cancer 2019 08 13;7(1):216. Epub 2019 Aug 13.

Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.

Background: Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors.

Methods: Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence.

Results: We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8 T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8 effector T cells.

Conclusions: Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors.
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http://dx.doi.org/10.1186/s40425-019-0698-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693252PMC
August 2019

High Salt Inhibits Tumor Growth by Enhancing Anti-tumor Immunity.

Front Immunol 2019 4;10:1141. Epub 2019 Jun 4.

VIB Laboratory of Translational Immunomodulation, VIB Center for Inflammation Research, University of Hasselt, Campus Diepenbeek, Hasselt, Belgium.

Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function . Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2019.01141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557976PMC
October 2020

Unleashing Tumour-Dendritic Cells to Fight Cancer by Tackling Their Three A's: Abundance, Activation and Antigen-Delivery.

Cancers (Basel) 2019 May 14;11(5). Epub 2019 May 14.

Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, 1050 Brussels, Belgium.

Recent advances in cancer immunotherapy have mainly focused on re-activating T-cell responses against cancer cells. However, both priming and activation of effector T-cell responses against cancer-specific antigens require cross-talk with dendritic cells (DCs), which are responsible for the capturing, processing and presentation of tumour-(neo)antigens to T cells. DCs consequently constitute an essential target in efforts to generate therapeutic immunity against cancer. This review will discuss recent research that is unlocking the cancer-fighting potential of tumour-infiltrating DCs. First, the complexity of DCs in the tumour microenvironment regarding the different subsets and the difficulty of translating mouse data into equivalent human data will be briefly touched upon. Mainly, possible solutions to problems currently faced in DC-based cancer treatments will be discussed, including their infiltration into tumours, activation strategies, and antigen delivery methods. In this way, we hope to put together a broad picture of potential synergistic therapies that could be implemented to harness the full capacity of tumour-infiltrating DCs to stimulate anti-tumour immune responses in patients.
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http://dx.doi.org/10.3390/cancers11050670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562396PMC
May 2019

Clinical Translation of [Ga]Ga-NOTA-anti-MMR-sdAb for PET/CT Imaging of Protumorigenic Macrophages.

Mol Imaging Biol 2019 10;21(5):898-906

In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium.

Purpose: Macrophage mannose receptor (MMR, CD206) expressing tumor-associated macrophages (TAM) are protumorigenic and was reported to negatively impact therapy responsiveness and is associated with higher chances of tumor relapse following multiple treatment regimens in preclinical tumor models. Since the distribution of immune cells within the tumor is often heterogeneous, sampling "errors" using tissue biopsies will occur. In order to overcome this limitation, we propose positron emission tomography (PET)/X-ray computed tomography (CT) imaging using Ga-labeled anti-MMR single-domain antibody fragment (sdAb) to assess the presence of these protumorigenic TAM.

Procedures: Cross-reactive anti-MMR-sdAb was produced according to good manufacturing practice (GMP) and conjugated to p-SCN-Bn-NOTA bifunctional chelator for Ga-labeling. Biodistribution and PET/CT studies were performed in wild-type and MMR-deficient 3LL-R tumor-bearing mice. Biodistribution data obtained in mice were extrapolated to calculate radiation dose estimates for the human adult using OLINDA software. A 7-day repeated dose toxicity study for NOTA-anti-MMR-sdAb was performed in healthy mice up to a dose of 1.68 mg/kg.

Results: [Ga]Ga-NOTA-anti-MMR-sdAb was obtained with 76 ± 2 % radiochemical yield, 99 ± 1 % radiochemical purity, and apparent molar activity of 57 ± 11 GBq/μmol. In vivo biodistribution analysis showed fast clearance via the kidneys and retention in MMR-expressing organs and tumor, with tumor-to-blood and tumor-to-muscle ratios of 6.80 ± 0.62 and 5.47 ± 1.82, respectively. The calculated effective dose was 0.027 mSv/MBq and 0.034 mSv/MBq for male and female, respectively, which means that a proposed dose of 185 MBq in humans would yield a radiation dose of 5.0 and 6.3 mSv to male and female patients, respectively. In the toxicity study, no adverse effects were observed.

Conclusions: Preclinical validation of [Ga]Ga-NOTA-anti-MMR-sdAb showed high specific uptake of this tracer in MMR-expressing TAM and organs, with no observed toxicity. [Ga]Ga-NOTA-anti-MMR-sdAb is ready for a phase I clinical trial.
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http://dx.doi.org/10.1007/s11307-018-01302-5DOI Listing
October 2019

Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy.

J Immunother Cancer 2019 01 15;7(1):10. Epub 2019 Jan 15.

Department of Otolaryngology-Head and Neck surgery, Baylor College of Medicine, Houston, TX, USA.

Background: Chemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects.

Methods: Therefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes.

Results: We show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8 T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8 T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner.

Conclusions: Overall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation.
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http://dx.doi.org/10.1186/s40425-018-0485-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332704PMC
January 2019

Adoptive Transfer of Monocytes Sorted from Bone Marrow.

Bio Protoc 2019 Jan 5;9(1):e3134. Epub 2019 Jan 5.

Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.

Inflammatory Ly6C monocytes can give rise to distinct mononuclear myeloid cells in the tumor microenvironment, such as monocytic myeloid-derived suppressor cells (Mo-MDSC), immature macrophages, M2-like tumor-associated macrophages (TAMs), M1-like TAMs or monocyte-derived dendritic cells (Mo-DCs). This protocol describes a method to assess the fate and recruitment of inflammatory Ly6C monocytes in the tumor microenvironment.
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http://dx.doi.org/10.21769/BioProtoc.3134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854204PMC
January 2019

Diamonds in the Rough: Harnessing Tumor-Associated Myeloid Cells for Cancer Therapy.

Front Immunol 2018 8;9:2250. Epub 2018 Oct 8.

Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.

Therapeutic approaches that engage immune cells to treat cancer are becoming increasingly utilized in the clinics and demonstrated durable clinical benefit in several solid tumor types. Most of the current immunotherapies focus on manipulating T cells, however, the tumor microenvironment (TME) is abundantly infiltrated by a heterogeneous population of tumor-associated myeloid cells, including tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). Educated by signals perceived in the TME, these cells often acquire tumor-promoting properties ultimately favoring disease progression. Upon appropriate stimuli, myeloid cells can exhibit cytoxic, phagocytic, and antigen-presenting activities thereby bolstering antitumor immune responses. Thus, depletion, reprogramming or reactivation of myeloid cells to either directly eradicate malignant cells or promote antitumor T-cell responses is an emerging field of interest. In this review, we briefly discuss the tumor-promoting and tumor-suppressive roles of myeloid cells in the TME, and describe potential therapeutic strategies in preclinical and clinical development that aim to target them to further expand the range of current treatment options.
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http://dx.doi.org/10.3389/fimmu.2018.02250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186813PMC
September 2019

Myeloid cell heterogeneity in cancer: not a single cell alike.

Cell Immunol 2018 08 14;330:188-201. Epub 2018 Feb 14.

Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; Laboratory of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium. Electronic address:

Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on antitumor immunity and influence fundamental processes that underlie malignancy, including neoangiogenesis, sustained cancer cell proliferation, metastasis and therapy resistance. For these reasons, development of therapeutic approaches to deplete or reprogram myeloid cells in cancer is an emerging field of interest. However, knowledge about the heterogeneity of myeloid cells in tumors and their variability between patients and disease stages is still limited. In this review, we summarize the most recent advances in our understanding about how the phenotype of tumor-associated macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells is dictated by their ontogeny, activation status and localization. We also outline major open questions that will only be resolved by applying high-dimensional single-cell technologies and systems biology approaches in the analysis of the tumor microenvironment.
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http://dx.doi.org/10.1016/j.cellimm.2018.02.008DOI Listing
August 2018

Beyond the M-CSF receptor - novel therapeutic targets in tumor-associated macrophages.

FEBS J 2018 02 6;285(4):777-787. Epub 2017 Sep 6.

Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.

Tumor-associated macrophages (TAM) are by now established as important regulators of tumor progression by impacting on tumor immunity, angiogenesis, and metastasis. Hence, a multitude of approaches are currently pursued to intervene with TAM's protumor activities, the most advanced of which being a blockade of macrophage-colony stimulating factor (M-CSF)/M-CSF receptor (M-CSFR) signaling. M-CSFR signaling largely impacts on the differentiation of macrophages, including TAM, and hence strongly influences the numbers of these cells in tumors. However, a repolarization of TAM toward a more antitumor phenotype may be more elegant and may yield stronger effects on tumor growth. In this respect, several aspects of TAM behavior could be altered, such as their intratumoral localization, metabolism and regulatory pathways. Intervention strategies could include the use of small molecules but also new generations of biologicals which may complement the current success of immune checkpoint blockers. This review highlights current work on the search for new therapeutic targets in TAM.
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http://dx.doi.org/10.1111/febs.14202DOI Listing
February 2018

CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus.

Gut 2017 12 14;66(12):2098-2109. Epub 2017 Jun 14.

Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.

Objective: Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility.

Design: IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MΦs) during onset and resolution of ME inflammation.

Results: At early time points, IM-induced GI transit delay and inflammation were equal in WT and mice. However, GI transit recovery after IM was significantly delayed in mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MΦs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MΦ colony-stimulating factor 1 enhanced monocyte recruitment and MΦ differentiation and ameliorated GI transit in mice.

Conclusion: Our study reveals a critical role for monocyte-derived MΦs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ physiological repair functions.
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http://dx.doi.org/10.1136/gutjnl-2016-313144DOI Listing
December 2017

Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade.

Sci Transl Med 2017 04;9(385)

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma. Mechanistically, A2V promoted vascular regression, tumor necrosis, and antigen presentation by intratumoral phagocytes. A2V also normalized the remaining blood vessels and facilitated the extravasation and perivascular accumulation of activated, interferon-γ (IFNγ)-expressing CD8 cytotoxic T lymphocytes (CTLs). Whereas the antitumoral activity of A2V was, at least partly, CTL-dependent, perivascular T cells concurrently up-regulated the expression of the immune checkpoint ligand programmed cell death ligand 1 (PD-L1) in tumor endothelial cells. IFNγ neutralization blunted this adaptive response, and PD-1 blockade improved tumor control by A2V in different cancer models. These findings position immune cells as key effectors of antiangiogenic therapy and support the rationale for cotargeting angiogenesis and immune checkpoints in cancer therapy.
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http://dx.doi.org/10.1126/scitranslmed.aak9670DOI Listing
April 2017

Exploiting tumor-associated dendritic cell heterogeneity for novel cancer therapies.

J Leukoc Biol 2017 08 7;102(2):317-324. Epub 2017 Apr 7.

Myeloid Cell Immunology Lab, VIB-UGent Center for Inflammation Research, Ghent, Belgium; and.

Dendritic cells (DCs) are specialized APCs present in all tissues, including tumors. They play a major role in orchestrating immune responses and were shown to occur in various functional states in tumors. In this respect, immunogenic tumor-associated DCs (TADCs) are required to initiate and sustain T cell-dependent anti-cancer immunity, whereas regulatory TADCs harbor robust immunosuppressive potential and accelerate malignant growth. Importantly, the heterogeneity of the DC compartment in tumors has been dissected recently in murine and human cancers and was shown to consist of developmentally distinct subsets, including conventional DC (cDC)1, cDC2, and monocyte-derived DCs (Mo-DCs). TADCs constitute an essential target in efforts to generate therapeutic immunity against cancer, and the understanding of the complexity of the TADC heterogeneity might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors. Hence, this review addresses the differential functional specializations of ontogenically distinct TADC subsets.
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http://dx.doi.org/10.1189/jlb.4MR1116-466RDOI Listing
August 2017

The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity.

Nat Commun 2016 12 23;7:13720. Epub 2016 Dec 23.

Laboratory of Myeloid Cell Immunology, VIB Inflammation Research Center, 9000 Ghent, Belgium.

Various steady state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1s, cDC2s and monocyte-derived DCs, displaying differential functional specializations. The identification of functionally distinct tumour-associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumours as well as human tumours harbour ontogenically discrete TADC subsets. Monocyte-derived TADCs are prominent in tumour antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADCs have lymph node migratory potential, whereby cDC1s efficiently activate CD8 T cells and cDC2s induce Th17 cells. Mice vaccinated with cDC2s displayed a reduced tumour growth accompanied by a reprogramming of pro-tumoural TAMs and a reduction of MDSCs, while cDC1 vaccination strongly induces anti-tumour CTLs. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors.
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http://dx.doi.org/10.1038/ncomms13720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5196231PMC
December 2016

Novel insights in the regulation and function of macrophages in the tumor microenvironment.

Curr Opin Oncol 2017 01;29(1):55-61

aLaboratory of Myeloid Cell Immunology, VIB Inflammation Research Center, Ghent bLaboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.

Purpose Of Review: Tumors contain not only cancer cells but also nontransformed types of cells, the stromal cells. A bidirectional interplay exists between transformed and nontransformed cells leading to tumor progression and metastasis. Tumor-associated macrophages (TAMs) are the most abundant tumor-infiltrating leukocytes characterized by a high heterogeneity and plasticity. TAMs exhibit strong protumoral activities and are related to bad prognosis and worse overall survival in various cancer types.

Recent Findings: Recent progress has delineated the existence of distinct TAM subsets in primary tumors and metastatic sites regulated by diverse mechanisms and triggering strong protumoral functions such as immunossuppression, angiogenesis, metastasis and resistance to current therapies.

Summary: Delineating the regulatory pathways governing TAM heterogeneity and activation could present a novel frontier in cancer therapy. TAM targeting/repolarization is considered as a promising novel therapeutic modality in combination with standard-of-care therapies or immuno checkpoint blockers.
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http://dx.doi.org/10.1097/CCO.0000000000000344DOI Listing
January 2017

Suppression of microRNA activity amplifies IFN-γ-induced macrophage activation and promotes anti-tumour immunity.

Nat Cell Biol 2016 07 13;18(7):790-802. Epub 2016 Jun 13.

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

Tumour-associated macrophages (TAMs) largely express an alternatively activated (or M2) phenotype, which entails immunosuppressive and tumour-promoting capabilities. Reprogramming TAMs towards a classically activated (M1) phenotype may thwart tumour-associated immunosuppression and unleash anti-tumour immunity. Here we show that conditional deletion of the microRNA (miRNA)-processing enzyme DICER in macrophages prompts M1-like TAM programming, characterized by hyperactive IFN-γ/STAT1 signalling. This rewiring abated the immunosuppressive capacity of TAMs and fostered the recruitment of activated cytotoxic T lymphocytes (CTLs) to the tumours. CTL-derived IFN-γ exacerbated M1 polarization of Dicer1-deficient TAMs and inhibited tumour growth. Remarkably, DICER deficiency in TAMs negated the anti-tumoral effects of macrophage depletion by anti-CSF1R antibodies, and enabled complete tumour eradication by PD1 checkpoint blockade or CD40 agonistic antibodies. Finally, genetic rescue of Let-7 miRNA activity in Dicer1-deficient TAMs partly restored their M2-like phenotype and decreased tumour-infiltrating CTLs. These findings suggest that DICER/Let-7 activity opposes IFN-γ-induced, immunostimulatory M1-like TAM activation, with potential therapeutic implications.
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http://dx.doi.org/10.1038/ncb3371DOI Listing
July 2016

M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment.

Cancer Res 2016 Jan 16;76(1):35-42. Epub 2015 Nov 16.

Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium. Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.

Tumors contain a heterogeneous myeloid fraction comprised of discrete MHC-II(hi) and MHC-II(lo) tumor-associated macrophage (TAM) subpopulations that originate from Ly6C(hi) monocytes. However, the mechanisms regulating the abundance and phenotype of distinct TAM subsets remain unknown. Here, we investigated the role of macrophage colony-stimulating factor (M-CSF) in TAM differentiation and polarization in different mouse tumor models. We demonstrate that treatment of tumor-bearing mice with a blocking anti-M-CSFR monoclonal antibody resulted in a reduction of mature TAMs due to impaired recruitment, extravasation, proliferation, and maturation of their Ly6C(hi) monocytic precursors. M-CSFR signaling blockade shifted the MHC-II(lo)/MHC-II(hi) TAM balance in favor of the latter as observed by the preferential differentiation of Ly6C(hi) monocytes into MHC-II(hi) TAMs. In addition, the genetic and functional signatures of MHC-II(lo) TAMs were downregulated upon M-CSFR blockade, indicating that M-CSFR signaling shapes the MHC-II(lo) TAM phenotype. Conversely, granulocyte macrophage (GM)-CSFR had no effect on the mononuclear tumor infiltrate or relative abundance of TAM subsets. However, GM-CSFR signaling played an important role in fine-tuning the MHC-II(hi) phenotype. Overall, our data uncover the multifaceted and opposing roles of M-CSFR and GM-CSFR signaling in governing the phenotype of macrophage subsets in tumors, and provide new insight into the mechanism of action underlying M-CSFR blockade.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-0869DOI Listing
January 2016

E-cadherin expression in macrophages dampens their inflammatory responsiveness in vitro, but does not modulate M2-regulated pathologies in vivo.

Sci Rep 2015 Jul 31;5:12599. Epub 2015 Jul 31.

1] Laboratory of Myeloid Cell Immunology, VIB, Brussels, Belgium [2] Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.

IL-4/IL-13-induced alternatively activated macrophages (M(IL-4/IL-13), AAMs or M2) are known to express E-cadherin, enabling them to engage in heterotypic cellular interactions and IL-4-driven macrophage fusion in vitro. Here we show that E-cadherin overexpression in Raw 264.7 macrophages inhibits their inflammatory response to LPS stimulation, as demonstrated by a reduced secretion of inflammatory mediators like interleukin (IL)-6, tumor necrosis factor (TNF) and nitric oxide (NO). To study the function of E-cadherin in M(IL-4/IL-13) macrophages in vivo, we generated macrophage-specific E-cadherin-deficient C57BL/6 mice. Using this new tool, we analyzed immunological parameters during two typical AAM-associated Th2-driven diseases and assessed Th2-associated granuloma formation. Although E-cadherin is strongly induced in AAMs during Taenia crassiceps helminth infections and allergic airway inflammation, its deletion in macrophages does not affect the course of both Th2 cytokine-driven diseases. Moreover, macrophage E-cadherin expression is largely redundant for granuloma formation around Schistosoma mansoni ova. Overall, we conclude that E-cadherin is a valuable AAM marker which suppresses the inflammatory response when overexpressed. Yet E-cadherin deletion in macrophages does not affect M(LPS+IFNγ) and M(IL-4) polarization in vitro, nor in vivo macrophage function, at least in the conditions tested.
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http://dx.doi.org/10.1038/srep12599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521155PMC
July 2015

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

Biochim Biophys Acta 2016 Jan 2;1865(1):23-34. Epub 2015 Jul 2.

Myeloid Cell Immunology Lab, VIB, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address:

The tumor-promoting role of macrophages has been firmly established in most cancer types. However, macrophage identity has been a matter of debate, since several levels of complexity result in considerable macrophage heterogeneity. Ontogenically, tissue-resident macrophages derive from yolk sac progenitors which either directly or via a fetal liver monocyte intermediate differentiate into distinct macrophage types during embryogenesis and are maintained throughout life, while a disruption of the steady state mobilizes monocytes and instructs the formation of monocyte-derived macrophages. Histologically, the macrophage phenotype is heavily influenced by the tissue microenvironment resulting in molecularly and functionally distinct macrophages in distinct organs. Finally, a change in the tissue microenvironment as a result of infectious or sterile inflammation instructs different modes of macrophage activation. These considerations are relevant in the context of tumors, which can be considered as sites of chronic sterile inflammation encompassing subregions with distinct environmental conditions (for example, hypoxic versus normoxic). Here, we discuss existing evidence on the role of macrophage subpopulations in steady state tissue and primary tumors of the breast, lung, pancreas, brain and liver.
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http://dx.doi.org/10.1016/j.bbcan.2015.06.009DOI Listing
January 2016

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

J Nucl Med 2015 Aug 11;56(8):1265-71. Epub 2015 Jun 11.

In Vivo Cellular and Molecular Imaging laboratory (ICMI), Vrije Universiteit Brussel, Brussels, Belgium Department of Nuclear Medicine, UZ Brussel, Brussels, Belgium; and.

Unlabelled: 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: Cross-reactive 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 MMR-expressing 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.
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http://dx.doi.org/10.2967/jnumed.115.156828DOI Listing
August 2015

Ly6C- Monocytes Regulate Parasite-Induced Liver Inflammation by Inducing the Differentiation of Pathogenic Ly6C+ Monocytes into Macrophages.

PLoS Pathog 2015 May 28;11(5):e1004873. Epub 2015 May 28.

Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB), Brussels, Belgium; Cellular and Molecular Immunology Unit, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

Monocytes consist of two well-defined subsets, the Ly6C+ and Ly6C- monocytes. Both CD11b+ myeloid cells populations have been proposed to infiltrate tissues during inflammation. While infiltration of Ly6C+ monocytes is an established pathogenic factor during hepatic inflammation, the role of Ly6C- monocytes remains elusive. Mice suffering experimental African trypanosome infection die from systemic inflammatory response syndrome (SIRS) that is initiated by phagocytosis of parasites by liver myeloid cells and culminates in apoptosis/necrosis of liver myeloid and parenchymal cells that reduces host survival. C57BL/6 mice are considered as trypanotolerant to Trypanosoma congolense infection. We have reported that in these animals, IL-10, produced among others by myeloid cells, limits the liver damage caused by pathogenic TNF-producing Ly6C+ monocytes, ensuring prolonged survival. Here, the heterogeneity and dynamics of liver myeloid cells in T. congolense-infected C57/BL6 mice was further dissected. Moreover, the contribution of Ly6C- monocytes to trypanotolerance was investigated. By using FACS analysis and adoptive transfer experiments, we found that the accumulation of Ly6C- monocytes and macrophages in the liver of infected mice coincided with a drop in the pool of Ly6C+ monocytes. Pathogenic TNF mainly originated from Ly6C+ monocytes while Ly6C- monocytes and macrophages were major and equipotent sources of IL-10 within myeloid cells. Moreover, Nr4a1 (Nur77) transcription factor-dependent Ly6C- monocytes exhibited IL-10-dependent and cell contact-dependent regulatory properties contributing to trypanotolerance by suppressing the production of TNF by Ly6C+ monocytes and by promoting the differentiation of the latter cells into macrophages. Thus, Ly6C- monocytes can dampen liver damage caused by an extensive Ly6C+ monocyte-associated inflammatory immune response in T. congolense trypanotolerant animals. In a more general context, Ly6C- or Ly6C+ monocyte targeting may represent a therapeutic approach in liver pathogenicity induced by chronic infection.
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http://dx.doi.org/10.1371/journal.ppat.1004873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447383PMC
May 2015

Molecular profiling reveals a tumor-promoting phenotype of monocytes and macrophages in human cancer progression.

Immunity 2014 Nov 30;41(5):815-29. Epub 2014 Oct 30.

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore 138648, Singapore. Electronic address:

Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target.
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http://dx.doi.org/10.1016/j.immuni.2014.09.014DOI Listing
November 2014