In-Depth Immune-Oncology Studies of the Tumor Microenvironment in a Humanized Melanoma Mouse Model

The presence and interaction of immune cells in the tumor microenvironment is of significant importance and has a great impact on disease progression and response to therapy. Hence, their identification is of high interest for prognosis and treatment decisions. Besides detailed phenotypic analyses of immune, as well as tumor cells, spatial analyses is an important parameter in the complex interplay of neoplastic and immune cells—especially when moving into focus efforts to develop and validate new therapeutic strategies. Ex vivo analysis of tumor samples by immunohistochemistry staining methods conserves spatial information is restricted to single markers, while flow cytometry (disrupting tissue into single cell suspensions) provides access to markers in larger numbers. Nevertheless, this comes at the cost of scarifying morphological information regarding tissue localization and cell–cell contacts. Further detrimental effects incurred by, for example, tissue digestion include staining artifacts. Consequently, ongoing efforts are directed towards methods that preserve, completely or in part, spatial information, while increasing the number of markers that can potentially be interrogated to the level of conventional flow cytometric methods. Progression in multiplex immunohistochemistry in the last ten years overcame the limitation to 1–2 markers in classical staining methods using DAB with counter stains or even pure chemical staining methods. In this study, we compared the multiplex method Chipcytometry to flow cytometry and classical IHC-P using DAB and hematoxylin. Chipcytometry uses frozen or paraffin-embedded tissue sections stained with readily available commercial fluorophore-labeled antibodies in repetitive cycles of staining and bleaching. The iterative staining approach enables sequential analysis of a virtually unlimited number of markers on the same sample, thereby identifying immune cell subpopulations in the tumor microenvironment in the present study in a humanized mouse melanoma model.

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Chemokine-Directed Tumor Microenvironment Modulation in Cancer Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms22189804 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9804

Author(s):

Pedro Bule ◽

Sandra I. Aguiar ◽

Frederico Aires-Da-Silva ◽

Joana N. R. Dias

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Immune Cell ◽

Vascular Endothelial Cells ◽

Tumor Biology ◽

Large Family ◽

Response To Therapy ◽

Cell Trafficking ◽

Immunotherapy Target ◽

Patient Prognosis

Chemokines are a large family of small chemotactic cytokines that coordinates immune cell trafficking. In cancer, they have a pivotal role in the migration pattern of immune cells into the tumor, thereby shaping the tumor microenvironment immune profile, often towards a pro-tumorigenic state. Furthermore, chemokines can directly target non-immune cells in the tumor microenvironment, including cancer, stromal and vascular endothelial cells. As such, chemokines participate in several cancer development processes such as angiogenesis, metastasis, cancer cell proliferation, stemness and invasiveness, and are therefore key determinants of disease progression, with a strong influence in patient prognosis and response to therapy. Due to their multifaceted role in the tumor immune response and tumor biology, the chemokine network has emerged as a potential immunotherapy target. Under the present review, we provide a general overview of chemokine effects on several tumoral processes, as well as a description of the currently available chemokine-directed therapies, highlighting their potential both as monotherapy or in combination with standard chemotherapy or other immunotherapies. Finally, we discuss the most critical challenges and prospects of developing targeted chemokines as therapeutic options.

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S100A9-Imaging Enables Estimation of Early Therapy-Mediated Changes in the Inflammatory Tumor Microenvironment

Biomedicines ◽

10.3390/biomedicines9010029 ◽

2021 ◽

Vol 9 (1) ◽

pp. 29

Author(s):

Anne Helfen ◽

Annika Schnepel ◽

Jan Rieß ◽

Miriam Stölting ◽

Mirjam Gerwing ◽

...

Keyword(s):

Flow Cytometry ◽

Tumor Microenvironment ◽

Tumor Size ◽

Immune Cell ◽

Ex Vivo ◽

Cell Activity ◽

Imaging Biomarker ◽

Early Therapy ◽

Imaging Results

(1) Background: The prognosis of cancer is dependent on immune cells in the tumor microenvironment (TME). The protein S100A9 is an essential regulator of the TME, associated with poor prognosis. In this study, we evaluated early therapy effects on the TME in syngeneic murine breast cancer via S100A9-specific in vivo imaging. (2) Methods: Murine 4T1 cells were implanted orthotopically in female BALB/c mice (n = 59). Tumor size-adapted fluorescence imaging was performed before and 5 days after chemo- (Doxorubicin, n = 20), anti-angiogenic therapy (Bevacizumab, n = 20), or placebo (NaCl, n = 19). Imaging results were validated ex vivo (immunohistochemistry, flow cytometry). (3) Results: While tumor growth revealed no differences (p = 0.48), fluorescence intensities (FI) for S100A9 in Bevacizumab-treated tumors were significantly lower as compared to Doxorubicin (2.60 vs. 15.65 AU, p < 0.0001). FI for Doxorubicin were significantly higher compared to placebo (8.95 AU, p = 0.01). Flow cytometry revealed shifts in monocytic and T-cell cell infiltrates under therapy, correlating with imaging. (4) Conclusions: S100A9-specific imaging enables early detection of therapy effects visualizing immune cell activity in the TME, even before clinically detectable changes in tumor size. Therefore, it may serve as a non-invasive imaging biomarker for early therapy effects.

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557 Determining the efficacy of ADCC by the 3D-EX ex vivo platform utilizing tumoroids of fresh patient tumor samples with intact tumor microenvironment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0557 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A591-A591

Author(s):

Jenny Kreahling ◽

Jared Ehrhart ◽

Stephen Iwanowycz ◽

Mibel Pabon ◽

Tina Pastoor ◽

...

Keyword(s):

Cell Death ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Immune Cells ◽

Immune Cell ◽

Ex Vivo ◽

Cell Killing ◽

Confocal Imaging ◽

Tumor Cell Death ◽

Tumor Cell Killing

BackgroundAntibody-dependent cell-mediated cytotoxicity (ADCC) is an effective tool where antibody-coated cells are targeted and killed by effector immune cells. The application of ADCC therapies has been expanded for both solid tumors as well as hematologic malignancies. However, the immunosuppressive mechanisms present in the immune tumor microenvironment (TME) pose a formidable challenge to immune cell efficacy in addition to hinderance of immune cell infiltration by tumor stromal elements. Hence, it is important to develop clinically relevant platforms to assess the efficacy of antibodies for ADCC. Here we utilized our 3D-EX platform using tumoroids of fresh patient tumor samples to assess ADCC-mediated tumor cell killing.MethodsAll human tumor samples were obtained with proper patient consent and IRB approval. Fresh patient tumor tissue of various histologic types including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) was processed to generate uniform sized live 3D tumoroids measuring 150 µm in size. Treatment groups included cetuximab alone or in combination with nivolumab and/or ipilimumab. Culture supernatants were collected for multiplex analysis of cytokine release in media. Multiplex flow cytometry was used to assess the activation profile of tumor resident immune cells in combination with high-content confocal imaging to determine extent of ADCC-mediated tumor cell death in the intact tumor extracellular matrix.ResultsUsing fresh patient-derived tumor organoids, we observed ADCC-dependent death of EGFR expressing tumor cells. Flow cytometric analysis of immune cell populations demonstrated treatment mediated activation of resident immune cells, which coincided with cytokine profiles determined by Luminex multiplex cytokine analysis. Additionally, tumor cell killing observed through high-content confocal imaging and quantitative image analysis showed tumor cell death with the 3D tumoroids.ConclusionsIn this comprehensive study we demonstrate that the 3D-EX ex vivo model is a robust system to assess the efficacy of ADCC and to develop novel therapeutic combinations with other immuno-oncology therapies. Furthermore, implementation of this platform in clinical studies may also allow for determination of the most effective combinatorial immuno-oncology therapy strategies for specialized individual patient care.Ethics ApprovalThe study was approved by Chesapeake IRB Pro00014313.

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492 Integration of high dimensional datasets in an immunocompetent mammary mouse model reveals pathways of tolerance and resistance to immune checkpoint blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0492 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A528-A528

Author(s):

Lin Ma ◽

Jian-Hua Mao ◽

Mary Helen Barcellos-Hoff ◽

Jade Moore

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Transforming Growth Factor ◽

Immune Cell ◽

Systemic Disease ◽

Ct Imaging ◽

High Dimensional ◽

Cytokine Signaling ◽

Immune Infiltrate ◽

Pet Ct

BackgroundCheckpoint inhibitors can induce robust and durable responses in a subset of patients. Extending this benefit to more patients could be facilitated by better understanding of how interacts with immune cells with the tumor microenvironment, which is a critical barrier to control both local and systemic disease. The composition and pattern of the immune infiltrate associates with the likelihood of response to immunotherapy. Inflamed tumors that exhibit a brisk immune cell infiltrate are responsive, while those in which immune cells are completely or partially excluded are not. Transforming growth factor β (TGFβ) is immunosuppressive and associated with the immune excluded phenotype.MethodsUsing an immune competent mammary tumor derived transplant (mTDT) model recently developed in our lab, exhibits inflamed, excluded or deserts immune infiltrate phenotypes based on localization of CD8 lymphocytes. Using whole transcriptome deep sequencing, cytof, and PET-CT imaging, we evaluated the tumor, microenvironment, and immune pathway activation among immune infiltrate phenotypes.ResultsThree distinct inflamed tumors phenotypes were identified: ‘classically’ inflamed characterized by pathway evidence of increased CD8+ T cells and decreased PD-L1 expression, inflamed tumors with pathways indicative of neovascularization and STAT3 signaling and reduced T cell mobilization, and an inflamed tumor with increased immunosuppressive myeloid phenotypes. Excluded tumors were characterized by TGFβ gene expression and pro-inflammatory cytokine signaling (e.g. TNFα, IL1β), associated with decreased leukocytes homing and increased immune cell death of cells. We visualized and quantified TGFβ activity using PET-CT imaging of 89Zr-fresolimumab, a TGFβ neutralizing antibody. TGFβ activity was significantly increased in excluded tumors compared to inflamed or desert tumors, which was supported by quantitative pathology (Perkin Elmer) of its canonical signaling target, phosphorylated SMAD2 (pSMAD2). pSMAD2 was positively correlated with PD-L1 expression in the stroma of excluded tumors. In contrast, in inflamed tumors, TGFβ activity positively correlated with increased F4/80 positive macrophages and negatively correlated with expression of PD-L1. CyTOF analysis of tumor and spleen immune phenotypes revealed increased trafficking of myeloid cells in mice bearing inflamed tumors compared to excluded and deserts.ConclusionsThe immunocompetent mTDT provides a model that bridges the gap between the immune landscape and tumor microenvironment. Integration of these high-dimensional data with further studies of response to immunotherapies will help to identify tumor features that favor response to treatment or the means to convert those that are unresponsive.

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When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

International Journal of Cell Biology ◽

10.1155/2011/470597 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 16

Author(s):

Katrin Schlie ◽

Jaeline E. Spowart ◽

Luke R. K. Hughson ◽

Katelin N. Townsend ◽

Julian J. Lum

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Patient Treatment ◽

Low Oxygen ◽

Tumor Environment ◽

And Function ◽

The Impact

Hypoxia is a signature feature of growing tumors. This cellular state creates an inhospitable condition that impedes the growth and function of all cells within the immediate and surrounding tumor microenvironment. To adapt to hypoxia, cells activate autophagy and undergo a metabolic shift increasing the cellular dependency on anaerobic metabolism. Autophagy upregulation in cancer cells liberates nutrients, decreases the buildup of reactive oxygen species, and aids in the clearance of misfolded proteins. Together, these features impart a survival advantage for cancer cells in the tumor microenvironment. This observation has led to intense research efforts focused on developing autophagy-modulating drugs for cancer patient treatment. However, other cells that infiltrate the tumor environment such as immune cells also encounter hypoxia likely resulting in hypoxia-induced autophagy. In light of the fact that autophagy is crucial for immune cell proliferation as well as their effector functions such as antigen presentation and T cell-mediated killing of tumor cells, anticancer treatment strategies based on autophagy modulation will need to consider the impact of autophagy on the immune system.

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In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment

Cells ◽

10.3390/cells10051020 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1020

Author(s):

Stefan Grote ◽

Guillermo Ureña-Bailén ◽

Kenneth Chun-Ho Chan ◽

Caroline Baden ◽

Markus Mezger ◽

...

Keyword(s):

Tumor Microenvironment ◽

Solid Tumors ◽

Immune Cells ◽

Immune Cell ◽

Nk Cell ◽

Migration And Invasion ◽

Cellular Immunotherapy ◽

Knock Out ◽

Immunosuppressive Tumor Microenvironment

Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond.

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822 GraphITE: unsupervised graph embeddings approach to multiplex immunofluorescence image exploration reveals new insights into NSCLC and HNSCC tumor microenvironment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.822 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A860-A860

Author(s):

Michael Surace ◽

Helen Angell ◽

Christopher Innocenti ◽

Zhenning Zhang ◽

Isabelle Gaffney ◽

...

Keyword(s):

Tumor Microenvironment ◽

Spatial Information ◽

Immune Cell ◽

Predictive Biomarkers ◽

Tumor Stroma ◽

List Type ◽

Graph Embeddings ◽

Cell Content ◽

Ffpe Tumor ◽

Image Exploration

BackgroundPredictive biomarkers for response to IO therapies remain insufficient. Although multiplex immunofluorescence has the potential to provide superior biomarkers, the information garnered from these studies is frequently underleveraged. Due to the large number of markers that must be analyzed (6 - 40 +), and the complexity of the spatial information, the number of hypotheses is large and must be tested systematically and automatically. GraphITE (Graphs-based Investigation of Tissues with Embeddings) is a novel method of converting multiplex IF image analysis results into embeddings, numerical vectors which represent the phenotype of each cell as well as the immediate neighborhood. This allows for the clustering of embeddings based on similarity as well as the discovery of novel predictive biomarkers based on both the spatial and multimarker data in multiplex IF images. Here we demonstrate initial observations from deployment of GraphITE on 564 commercially-sourced NSCLC and HNSCC resections stained with a multiplex IF panel containing CD8, PDL1, PD1, CD68, Ki67, and CK.Methods4 μm FFPE tumor sections were stained with CD8, PDL1, PD1, CD68, Ki67, and CK at Akoya Biosciences using OPAL TSA-linked fluorophores and imaged on a Vectra Polaris. Images were analyzed by Computational Biology (AstraZeneca). Graphs were built by mapping each cell in the mIF image as a node, using the X, Y coordinates and connecting nodes with edges according to distance. 64-dimensional embeddings were generated using Deep Graph InfoMax (DGI).1 Embeddings are downprojected to 2 dimensions using UMAP.2. Details are available in the preprint of the GraphITE methods manuscript.3ResultsA single downprojection was developed using embeddings from 158 HNSCC and 406 NSCLC cases. 60–80 distinct clusters were observed, some of which contained embeddings from both indications and others which were exclusive to one indication. Exclusive clusters describe tissue neighborhoods observed only in one indication. Drivers of cluster exclusivity included increased cell density in HNSCC as compared to NSCLC both in PD-L1- tumor centers with few infiltrating lymphocytes as well as in PD-L1- macrophagedominated neighborhoods. HNSCC and NSCLC embeddings were more colocalized in PD-L1+ tumor centers and in tumor stroma with high CD8+ or CD68+ immune cell content and high PD-L1+ expression.ConclusionsThis study demonstrates the utility and potential of the GraphITE platform to discriminate between and describe both unique and common neighborhood-level features of the tumor microenvironment. Deploying GraphITE across multiple indications effectively leverages spatial heterogeneity and multimarker information from multiplex IF panels.References1. Veličković P, Fedus W, Hamilton WL, Liò P, Bengio Y, DevonHjelm R. Deep Graph Infomax. 2018. arxiv:1809.10341 [stat.ML].2. McInnes L, Healy J, Melville J. UMAP: Uniform manifold approximationand projection for dimension reduction. 2020; arxiv:1802.03426 [stat.ML].3. Innocenti C, Zhang Z, Selvaraj B, Gaffney I, Frangos M, Cohen-Setton J, Dillon LAL, Surace MJ, Pedrinaci C, Hipp J, Baykaner K. An unsupervised graph embeddings approach to multiplex immunofluorescence image explorationbioRxiv 2021.06.09.447654; doi: https://doi.org/10.1101/2021.06.09.447654Ethics ApprovalThe study was approved by AstraZeneca.

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MIXTURE: an improved algorithm for immune tumor microenvironment estimation based on gene expression data

10.1101/726562 ◽

2019 ◽

Cited By ~ 3

Author(s):

Elmer A. Fernández ◽

Yamil D. Mahmoud ◽

Florencia Veigas ◽

Darío Rocha ◽

Mónica Balzarini ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cell ◽

Therapy Response ◽

Cell Types ◽

Gene Signature ◽

Response To Therapy ◽

Support Vector ◽

Data Sets ◽

Cell Type ◽

Before And After

AbstractRNA sequencing has proved to be an efficient high-throughput technique to robustly characterize the presence and quantity of RNA in tumor biopsies at a given time. Importantly, it can be used to computationally estimate the composition of the tumor immune infiltrate and to infer the immunological phenotypes of those cells. Given the significant impact of anti-cancer immunotherapies and the role of the associated immune tumor microenvironment (ITME) on its prognosis and therapy response, the estimation of the immune cell-type content in the tumor is crucial for designing effective strategies to understand and treat cancer. Current digital estimation of the ITME cell mixture content can be performed using different analytical tools. However, current methods tend to over-estimate the number of cell-types present in the sample, thus under-estimating true proportions, biasing the results. We developed MIXTURE, a noise-constrained recursive feature selection for support vector regression that overcomes such limitations. MIXTURE deconvolutes cell-type proportions of bulk tumor samples for both RNA microarray or RNA-Seq platforms from a leukocyte validated gene signature. We evaluated MIXTURE over simulated and benchmark data sets. It overcomes competitive methods in terms of accuracy on the true number of present cell-types and proportions estimates with increased robustness to estimation bias. It also shows superior robustness to collinearity problems. Finally, we investigated the human immune microenvironment of breast cancer, head and neck squamous cell carcinoma, and melanoma biopsies before and after anti-PD-1 immunotherapy treatment revealing associations to response to therapy which have not seen by previous methods.

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Using ex vivo culture to assess dynamic phenotype changes in human prostate macrophages following exposure to therapeutic drugs

Scientific Reports ◽

10.1038/s41598-021-98903-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Clovis Boibessot ◽

France-Hélène Joncas ◽

Aerin Park ◽

Zohra Berrehail ◽

Jean-François Pelletier ◽

...

Keyword(s):

Flow Cytometry ◽

Immune Cell ◽

Ex Vivo ◽

Cell Phenotype ◽

Gleason Grade ◽

Tumor Resistance ◽

Grade Group ◽

In Vivo Models ◽

Novel Associations

AbstractWithin the prostate tumor microenvironment (TME) there are complex multi-faceted and dynamic communication occurring between cancer cells and immune cells. Macrophages are key cells which infiltrate and surround tumor cells and are recognized to significantly contribute to tumor resistance and metastases. Our understanding of their function in the TME is commonly based on in vitro and in vivo models, with limited research to confirm these model observations in human prostates. Macrophage infiltration was evaluated within the TME of human prostates after 72 h culture of fresh biopsies samples in the presence of control or enzalutamide. In addition to immunohistochemistry, an optimized protocol for multi-parametric evaluation of cellular surface markers was developed using flow cytometry. Flow cytometry parameters were compared to clinicopathological features. Immunohistochemistry staining for 19 patients with paired samples suggested enzalutamide increased the expression of CD163 relative to CD68 staining. Techniques to validate these results using flow cytometry of dissociated biopsies after 72 h of culture are described. In a second cohort of patients with Gleason grade group ≥ 3 prostate cancer, global macrophage expression of CD163 was unchanged with enzalutamide treatment. However, exploratory analyses of our results using multi-parametric flow cytometry for multiple immunosuppressive macrophage markers suggest subgroup changes as well as novel associations between circulating biomarkers like the neutrophil to lymphocyte ratio (NLR) and immune cell phenotype composition in the prostate TME. Further, we observed an association between B7–H3 expressing tumor-associated macrophages and the presence of intraductal carcinoma. The use of flow cytometry to evaluate ex vivo cultured prostate biopsies fills an important gap in our ability to understand the immune cell composition of the prostate TME. Our results highlight novel associations for further investigation.

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Reprogramming of bone marrow myeloid progenitor cells in patients with severe coronary artery disease

eLife ◽

10.7554/elife.60939 ◽

2020 ◽

Vol 9 ◽

Author(s):

Marlies P Noz ◽

Siroon Bekkering ◽

Laszlo Groh ◽

Tim MJ Nielen ◽

Evert JP Lamfers ◽

...

Keyword(s):

Coronary Artery Disease ◽

Bone Marrow ◽

Coronary Artery ◽

Immune Cells ◽

Mononuclear Cells ◽

Immune Cell ◽

Ex Vivo ◽

Peripheral Blood Mononuclear ◽

Artery Disease ◽

Myeloid Progenitors

Atherosclerosis is the major cause of cardiovascular disease (CVD). Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. In patients with atherosclerotic CVD, leukocytes have a hyperinflammatory phenotype. We hypothesize that immune cell reprogramming in these patients occurs at the level of myeloid progenitors. We included 13 patients with coronary artery disease due to severe atherosclerosis and 13 subjects without atherosclerosis in an exploratory study. Cytokine production capacity after ex vivo stimulation of peripheral blood mononuclear cells (MNCs) and bone marrow MNCs was higher in patients with atherosclerosis. In BM-MNCs this was associated with increased glycolysis and oxidative phosphorylation. The BM composition was skewed towards myelopoiesis and transcriptome analysis of HSC/GMP cell populations revealed enrichment of neutrophil- and monocyte-related pathways. These results show that in patients with atherosclerosis, activation of innate immune cells occurs at the level of myeloid progenitors, which adds exciting opportunities for novel treatment strategies.

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