scholarly journals The Metabolic Control of Myeloid Cells in the Tumor Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2960
Author(s):  
Eloise Ramel ◽  
Sebastian Lillo ◽  
Boutaina Daher ◽  
Marina Fioleau ◽  
Thomas Daubon ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Phenotypic Diversity ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Mass Cytometry ◽  
Cell Functions ◽  
Metabolic Checkpoints ◽  
The Impact

Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell’s metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.

scholarly journals Single Cell Mass Cytometry Revealed the Immunomodulatory Effect of Cisplatin Via Downregulation of Splenic CD44+, IL-17A+ MDSCs and Promotion of Circulating IFN-γ+ Myeloid Cells in the 4T1 Metastatic Breast Cancer Model

2019 ◽  
Vol 21 (1) ◽  
pp. 170 ◽  
Author(s):  
József Á. Balog ◽  
László Hackler Jr. ◽  
Anita K. Kovács ◽  
Patrícia Neuperger ◽  
Róbert Alföldi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Cell ◽  
Cell Mass ◽  
Myeloid Cells ◽  
Metastatic Breast ◽  
Suppressor Cells ◽  
Immunomodulatory Effect ◽  
Mass Cytometry ◽  
Ifn Γ

The treatment of metastatic breast cancer remained a challenge despite the recent breakthrough in the immunotherapy regimens. Here, we addressed the multidimensional immunophenotyping of 4T1 metastatic breast cancer by the state-of-the-art single cell mass cytometry (CyTOF). We determined the dose and time dependent cytotoxicity of cisplatin on 4T1 cells by the xCelligence real-time electronic sensing assay. Cisplatin treatment reduced tumor growth, number of lung metastasis, and the splenomegaly of 4T1 tumor bearing mice. We showed that cisplatin inhibited the tumor stroma formation, the polarization of carcinoma-associated fibroblasts by the diminished proteolytic activity of fibroblast activating protein. The CyTOF analysis revealed the emergence of CD11b+/Gr-1+/CD44+ or CD11b+/Gr-1+/IL-17A+ myeloid-derived suppressor cells (MDSCs) and the absence of B220+ or CD62L+ B-cells, the CD62L+/CD4+ and CD62L+/CD8+ T-cells in the spleen of advanced cancer. We could show the immunomodulatory effect of cisplatin via the suppression of splenic MDSCs and via the promotion of peripheral IFN-γ+ myeloid cells. Our data could support the use of low dose chemotherapy with cisplatin as an immunomodulatory agent for metastatic triple negative breast cancer.

scholarly journals Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor Inflammation

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Michael C. Schmid ◽  
Judith A. Varner
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Angiogenesis ◽  
Malignant Tumors ◽  
Critical Role ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Promote Tumor Growth ◽  
Bone Marrow Derived Cells

Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. Furthermore, we describe a subset of myeloid cells with immunosuppressive activity (known as myeloid-derived suppressor cells). Finally, we will comment on the mechanisms regulating myeloid cell recruitment to the tumor microenvironment and on the potential of myeloid cells as new targets for cancer therapy.

scholarly journals IMMU-20. SINGLE-CELL RNASEQ OF TUMOR INFILTRATING IMMUNE CELLS FROM NEOADJUVANT ANTI-PD1 TREATED GBM PATIENTS REVEALS GLOBAL TRANSCRIPTIONAL CHANGES AND IMMUNOSUPPRESSIVE ADAPTIVE RESPONSES BY MYELOID CELLS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii109
Author(s):  
Alexander Lee ◽  
Aaron Mochizuki ◽  
Frances Chow ◽  
Jeremy Reynoso ◽  
Joey Orpilla ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Trajectory Analysis ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
Transcriptional Changes

Abstract INTRODUCTION Neoadjuvant anti-PD1 therapy (neo-aPD1) was previously shown to significantly increase the survival of recurrent glioblastoma patients in a small randomized clinical trial. However, neo-aPD1 alone was not curative so defining the limitations of neo-aPD1 and discovering where other immunotherapies can be used alongside neo-aPD1 is needed. METHODS To understand how immune cells in the tumor microenvironment change with neo-aPD1, we used single-cell RNAsequencing to analyze cells from 27 glioma patients (n = 105,143 cells) of which 9 patients had received neo-aPD1 (n = 33,325 cells). Using unsupervised clustering and pseudotime trajectory analysis, we characterized the transcriptional changes within immune cells and how these populations changed with therapy. RESULTS We defined the immune landscape of the glioblastoma tumor microenvironment. Compared to no immunotherapy treatment, neo-aPD1 significantly increased the ratio of T cells to myelo-monocytic cells and led to significant increases in the effector and memory T cell populations but no significant changes in myeloid cell composition. Our differential gene expression analysis of the myeloid compartment showed significant increases in interferon-γ-responsive genes and down-regulation of genes associated with M2 macrophages and MDSCs, suggestive that neo-aPD1 influences the transcriptional profile of myeloid cells in the tumor microenvironment. Interestingly, our psuedotime trajectory analysis showed that neo-aPD1 was associated with cells expressing both lymphoid and myeloid-related genes, which we theorized to actually be lymphoid-myeloid cell doublets caused by increased interactions between myeloid and lymphoid cells. These doublets were highly enriched in MHC I and II, macrophage, T cell, and T cell activation and exhaustion genes indicating that neo-aPD1 may result in some adaptive immunosuppressive mechanism by increasing these interactions. This could explain why neo-aPD1 alone is not curative for glioblastoma patients. CONCLUSIONS In total, neoadjuvant anti-PD1 therapy enhances effector T cell activity, but may concomitantly induce adaptive resistance mediated by myeloid cells in glioblastoma.

scholarly journals Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy

Blood ◽  
2010 ◽  
Vol 115 (7) ◽  
pp. 1461-1471 ◽  
Author(s):  
Saul J. Priceman ◽  
James L. Sung ◽  
Zory Shaposhnik ◽  
Jeremy B. Burton ◽  
Antoni X. Torres-Collado ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Antiangiogenic Therapy ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Compensatory Mechanism ◽  
Tumor Resistance ◽  
And Function ◽  
The Impact

Abstract Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b+F4/80+ tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b+Gr-1loLy6Chi mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti–VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

scholarly journals Inflammation and Cancer: Extra- and Intracellular Determinants of Tumor-Associated Macrophages as Tumor Promoters

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Gabor J. Szebeni ◽  
Csaba Vizler ◽  
Klara Kitajka ◽  
Laszlo G. Puskas
Keyword(s):  
Tumor Microenvironment ◽  
Macrophage Polarization ◽  
Myeloid Cells ◽  
Therapeutic Interventions ◽  
Tumor Associated Macrophages ◽  
Poor Survival ◽  
Cell Functions ◽  
Intracellular Signals ◽  
Ontogenetic Diversity ◽  
Cell Dissemination

One of the hallmarks of cancer-related inflammation is the recruitment of monocyte-macrophage lineage cells to the tumor microenvironment. These tumor infiltrating myeloid cells are educated by the tumor milieu, rich in cancer cells and stroma components, to exert functions such as promotion of tumor growth, immunosuppression, angiogenesis, and cancer cell dissemination. Our review highlights the ontogenetic diversity of tumor-associated macrophages (TAMs) and describes their main phenotypic markers. We cover fundamental molecular players in the tumor microenvironment including extra- (CCL2, CSF-1, CXCL12, IL-4, IL-13, semaphorins, WNT5A, and WNT7B) and intracellular signals. We discuss how these factors converge on intracellular determinants (STAT3, STAT6, STAT1, NF-κB, RORC1, and HIF-1α) of cell functions and drive the recruitment and polarization of TAMs. Since microRNAs (miRNAs) modulate macrophage polarization key miRNAs (miR-146a, miR-155, miR-125a, miR-511, and miR-223) are also discussed in the context of the inflammatory myeloid tumor compartment. Accumulating evidence suggests that high TAM infiltration correlates with disease progression and overall poor survival of cancer patients. Identification of molecular targets to develop new therapeutic interventions targeting these harmful tumor infiltrating myeloid cells is emerging nowadays.

scholarly journals Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity and Restricted Cytotoxic Effector Cell Trafficking and Activation During Malignant Progression in Glioma

2021 ◽  
Author(s):  
Sakthi Rajendran ◽  
Clayton Peterson ◽  
Alessandro Canella ◽  
Yang Hu ◽  
Amy Gross ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Malignant Progression ◽  
Low Grade ◽  
Cell Trafficking ◽  
High Grade ◽  
Single Cell Rna Sequencing

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

scholarly journals Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

2020 ◽  
Author(s):  
S. Mahnaz ◽  
L. Das Roy ◽  
M. Bose ◽  
C. De ◽  
S. Nath ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathways ◽  
Suppressor Cells ◽  
Ductal Adenocarcinoma ◽  
Myeloid Derived Suppressor Cells ◽  
Mucin 1 ◽  
Transmembrane Glycoprotein ◽  
The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi95
Author(s):  
Tyler Miller ◽  
Chadi El Farran ◽  
Julia Verga ◽  
Charles Couturier ◽  
Zeyu Chen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Myeloid Cell ◽  
Low Grade ◽  
Tumor Patients ◽  
The Many

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

scholarly journals Targeted deletion of PD-1 in myeloid cells induces antitumor immunity

2020 ◽  
Vol 5 (43) ◽  
pp. eaay1863 ◽  
Author(s):  
Laura Strauss ◽  
Mohamed A. A. Mahmoud ◽  
Jessica D. Weaver ◽  
Natalia M. Tijaro-Ovalle ◽  
Anthos Christofides ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Immunity ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effector Memory ◽  
Emergency Myelopoiesis

PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell–specific PD-1 ablation on antitumor immunity has remained unclear because most studies have used either PD-1–blocking antibodies or complete PD-1 KO mice. We generated a conditional allele, which allowed myeloid-specific (PD-1f/fLysMcre) or T cell–specific (PD-1f/fCD4cre) targeting of Pdcd1 gene. Compared with T cell–specific PD-1 ablation, myeloid cell–specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMPs), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSCs), express PD-1. In tumor-bearing PD-1f/fLysMcre but not PD-1f/fCD4cre mice, accumulation of GMP and MDSC was prevented, whereas systemic output of effector myeloid cells was increased. Myeloid cell–specific PD-1 ablation induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite preserved PD-1 expression in T cells. In PD-1–deficient myeloid progenitors, growth factors driving emergency myelopoiesis induced increased metabolic intermediates of glycolysis, pentose phosphate pathway, and TCA cycle but, most prominently, elevated cholesterol. Because cholesterol is required for differentiation of inflammatory macrophages and DC and promotes antigen-presenting function, our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade.

CNS myeloid cell heterogeneity at the single-cell level

Neuroforum ◽  
2019 ◽  
Vol 25 (3) ◽  
pp. 195-204
Author(s):  
Chotima Böttcher ◽  
Roman Sankowski ◽  
Josef Priller ◽  
Marco Prinz
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Myeloid Cell ◽  
Cellular Heterogeneity ◽  
Cell Heterogeneity ◽  
Mass Cytometry ◽  
Dynamic Regulation ◽  
The Central Nervous System ◽  
Disease Profiling ◽  
The Brain

Abstract The cellular composition of the central nervous system (CNS) is highly complex and dynamic. Regulation of this complexity is increasingly recognized to be spatially and temporally dependent during development, homeostasis and disease. Context-dependent cellular heterogeneity was shown for neuroectodermal cells as well as the myeloid compartment of the CNS. The brain myeloid compartment comprises microglia and other CNS-associated macrophages. These are brain-resident cells with critical roles in brain development, maintenance, and immune responses during states of disease. Profiling of CNS myeloid cell heterogeneity has been greatly facilitated in the past years by development of high-throughput technologies for single-cell analysis. This review summarizes current insights into heterogeneity of the CNS myeloid cell population determined by single-cell RNA sequencing and mass cytometry. The results offer invaluable insights into CNS biology and will facilitate the development of therapies for neurodegenerative and neuroinflammatory pathologies.

Sign in / Sign up

Export Citation Format

Share Document