Fatty Acid Metabolism in Myeloid-Derived Suppressor Cells and Tumor-Associated Macrophages: Key Factor in Cancer Immune Evasion

The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression.

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A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment

Cells ◽

10.3390/cells10102700 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2700

Author(s):

Francesca Hofer ◽

Gianna Di Sario ◽

Chiara Musiu ◽

Silvia Sartoris ◽

Francesco De Sanctis ◽

...

Keyword(s):

Metabolic Network ◽

Cancer Progression ◽

Immune Cells ◽

Energy Demand ◽

Tumour Progression ◽

Suppressor Cells ◽

Tumour Microenvironment ◽

Metabolic Reprogramming ◽

Myeloid Derived Suppressor Cells ◽

Cell Proliferation And Differentiation

Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression.

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Myeloid-Derived Suppressor Cells in Immune Microenvironment Promote Progression of Esophagogastric Junction Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.640080 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ying Wang ◽

Haiyan Sun ◽

Ningning Zhu ◽

Xianxian Wu ◽

Zhilin Sui ◽

...

Keyword(s):

Cancer Progression ◽

Immune Cells ◽

Esophagogastric Junction ◽

Immune Cell ◽

Suppressor Cells ◽

The Cancer Genome Atlas ◽

Low Grade ◽

Myeloid Derived Suppressor Cells ◽

M2 Macrophages ◽

Esophagogastric Junction Adenocarcinoma

Adenocarcinoma of the esophagogastric junction (AEG) is a fatal disease. Accumulating evidence indicates that, for a comprehensive understanding of AEG, studies should be conducted not only to investigate tumor cells, but also the tumor microenvironment (TME). In this study, we collected AEG patient data from The Cancer Genome Atlas, and used the CIBERSORT algorithm to analyze tumor-infiltrating immune cell profiles. The levels of CD8+ T cells and M0 and M2 macrophages were relatively high in AEG tissues. M2 macrophages were abundant in G3 tumors, and neutrophils were associated with poor prognosis. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immunosuppressive cells which share a similar origin to neutrophils and macrophages. We further analyzed the levels of MDSCs in AEG patients and healthy donors (HD) using flow cytometry. MDSC levels were elevated at tumor sites, with polymorphonuclear MDSCs (PMN-MDSCs) being the predominant subtype. Circulating MDSCs partly represented cells at the tumor site. We observed that PMN-MDSC levels at tumor sites were positively correlated with advanced staging, low grade, lymph node metastasis, and HER2− status. Immunohistochemistry and immunofluorescence analyses indicated that activation of the STAT3 and NF-κB pathways in MDSCs may be a potential mechanism for cancer progression. Our studies provided a comprehensive perspective involving tumor-infiltrating immune cells, and detailed insights into the proportion of MDSCs in AEG and their clinical significance. Together, these findings may improve our current understanding of cancer progression involving tumor-infiltrating immune cells in the TME.

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New Insights into the Multifaceted Role of Myeloid-Derived Suppressor Cells (MDSCs) in High-Grade Gliomas: From Metabolic Reprograming, Immunosuppression, and Therapeutic Resistance to Current Strategies for Targeting MDSCs

Cells ◽

10.3390/cells10040893 ◽

2021 ◽

Vol 10 (4) ◽

pp. 893

Author(s):

Senthilnath Lakshmanachetty ◽

Joselyn Cruz-Cruz ◽

Eric Hoffmeyer ◽

Allison P. Cole ◽

Siddhartha S. Mitra

Keyword(s):

Bone Marrow ◽

Immune Cells ◽

Suppressor Cells ◽

Standard Of Care ◽

High Grade Glioma ◽

Cell Types ◽

Current Treatment ◽

High Grade ◽

Myeloid Derived Suppressor Cells ◽

High Grade Gliomas

Cancer cells “hijack” host immune cells to promote growth, survival, and metastasis. The immune microenvironment of high-grade gliomas (HGG) is a complex and heterogeneous system, consisting of diverse cell types such as microglia, bone marrow-derived macrophages (BMDMs), myeloid-derived suppressor cells (MDSCs), dendritic cells, natural killer (NK) cells, and T-cells. Of these, MDSCs are one of the major tumor-infiltrating immune cells and are correlated not only with overall worse prognosis but also poor clinical outcomes. Upon entry from the bone marrow into the peripheral blood, spleen, as well as in tumor microenvironment (TME) in HGG patients, MDSCs deploy an array of mechanisms to perform their immune and non-immune suppressive functions. Here, we highlight the origin, function, and characterization of MDSCs and how they are recruited and metabolically reprogrammed in HGG. Furthermore, we discuss the mechanisms by which MDSCs contribute to immunosuppression and resistance to current therapies. Finally, we conclude by summarizing the emerging approaches for targeting MDSCs alone as a monotherapy or in combination with other standard-of-care therapies to improve the current treatment of high-grade glioma patients.

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Phenotypic shifts of tumor associated macrophages and STAT3 mediated suppression of myeloid derived suppressor cells drive sensitization of HER2+ tumor immunity

10.1101/2021.01.29.428708 ◽

2021 ◽

Author(s):

Dimitrios N. Sidiropoulos ◽

Christine Rafie ◽

Brian J. Christmas ◽

Emily F. Davis-Marcisak ◽

Gaurav Sharma ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Suppressor Cells ◽

Breast Tumors ◽

Cell Types ◽

Myeloid Derived Suppressor Cells ◽

Tumor Associated Macrophages ◽

Tumor Microenvironments ◽

Deacetylase Inhibitor ◽

M1 Phenotype ◽

Tumor Cell Killing

ABSTRACTUnderstanding how novel therapeutic combinations alter solid tumor microenvironments (TME) in immunosuppressive tumors such as breast cancer is essential to improve their responses to immune checkpoint inhibitors (ICIs). Entinostat, an oral histone deacetylase inhibitor (HDACi), has been shown to improve responses to ICIs in various tumor models with immunosuppressive TMEs, but the precise alterations induced by entinostat and mechanisms of synergy with ICIs remain unknown. Here, we employ single-cell RNA-sequencing on HER2 overexpressing breast tumors from mice treated with entinostat + ICIs to characterize these changes across cell types in the TME. This analysis demonstrates that treatment with entinostat induces a shift from a pro-tumor to an anti-tumor TME signature characterized predominantly by changes in the myeloid cells. Notably, myeloid-derived suppressor cells (MDSCs) are shifted toward the less suppressive granulocytic phenotype in association with reduced signaling through the STAT3 pathway. In addition, tumor-associated macrophages are shifted toward an anti-tumor M1 phenotype by epigenetic reprogramming. Overall, these entinostat-induced TME changes reduce immunosuppression and increase mechanisms of tumor cell killing to improve ICI responses and broaden the population of patients who could potentially benefit from immunotherapy.

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COX2/mPGES1/PGE2pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1612920114 ◽

2017 ◽

Vol 114 (5) ◽

pp. 1117-1122 ◽

Cited By ~ 147

Author(s):

Victor Prima ◽

Lyudmila N. Kaliberova ◽

Sergey Kaliberov ◽

David T. Curiel ◽

Sergei Kusmartsev

Keyword(s):

Bone Marrow ◽

Cancer Progression ◽

Bone Marrow Cells ◽

Myeloid Cells ◽

Suppressor Cells ◽

Prostaglandin E ◽

Tumor Escape ◽

Myeloid Derived Suppressor Cells ◽

Tumor Associated Macrophages

In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)–mediated inhibition of activated PD-1+T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti–PD-L1 and –PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow–derived myeloid cells. Tumor-induced expression of PD-L1 was limited to F4/80+macrophages and Ly-6C+myeloid-derived suppressor cells. These PD-L1–expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1+cells isolated from tumor-bearing mice also exerted morphology of tumor-associated macrophages and expressed high levels of prostaglandin E2(PGE2)-forming enzymes microsomal PGE2synthase 1 (mPGES1) and COX2. Inhibition of PGE2formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE2pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE2metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.

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The Enigma of Low-Density Granulocytes in Humans: Complexities in the Characterization and Function of LDGs during Disease

Pathogens ◽

10.3390/pathogens10091091 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1091

Author(s):

Brittany G. Seman ◽

Cory M. Robinson

Keyword(s):

Immune Cells ◽

Suppressor Cells ◽

Cell Types ◽

Low Density ◽

Myeloid Derived Suppressor Cells ◽

Disease States ◽

Isolation Techniques ◽

Microbial Infections ◽

And Function

Low-density granulocytes (LDGs) have been characterized as important immune cells during healthy and disease states in humans, including microbial infections, cancer, and autoimmune dysfunction. However, the classification of this cell type is similar to other immune cells (e.g., neutrophils, myeloid-derived suppressor cells) and ambiguous functional standards have rendered LDG identification and isolation daunting. Furthermore, most research involving LDGs has mainly focused on adult cells and subjects, leaving increased uncertainty surrounding younger populations, especially in vulnerable neonatal groups where LDG numbers are elevated. This review aims to bring together the current research in the field of LDG biology in the context of immunity to disease, with a focus on infection. In addition, we propose to highlight the gaps in the field that, if filled, could improve upon isolation techniques and functional characterizations for LDGs separate from neutrophils and myeloid-derived suppressor cells (MDSCs). This will not only enhance understanding of LDGs during disease processes and how they differ from other cell types but will also aid in the interpretation of comparative studies and results with the potential to inform development of novel therapeutics to improve disease states in patients.

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Terminating Cancer by Blocking VISTA as a Novel Immunotherapy: Hasta la vista, baby

Frontiers in Oncology ◽

10.3389/fonc.2021.658488 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ji-Eun Irene Yum ◽

Young-Kwon Hong

Keyword(s):

Monoclonal Antibody ◽

Clinical Trials ◽

T Cells ◽

Dendritic Cells ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Immune Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Checkpoint Molecule

VISTA is an up-and-coming immune checkpoint molecule that can become the target of new cancer immunotherapy treatments. Immune cells in the tumor microenvironment can largely influence the progression of cancer through inhibitory and stimulatory pathways. Indeed, VISTA is expressed on many immune cells, including T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. VISTA has predominantly been shown to act in an immune-suppressing manner that enables cancer progression. This review will delve into results from preclinical murine studies of anti-VISTA monoclonal antibody treatments, bring together recent studies that detect VISTA expression on immune cells from patient tumors of various cancers, and discuss ongoing clinical trials involving VISTA.

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Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Cancers ◽

10.3390/cancers11111627 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1627 ◽

Cited By ~ 5

Author(s):

Anita Thyagarajan ◽

Mamdouh Salman A. Alshehri ◽

Kelly L.R. Miller ◽

Catherine M. Sherwin ◽

Jeffrey B. Travers ◽

...

Keyword(s):

Survival Rates ◽

Suppressor Cells ◽

Cell Types ◽

Therapeutic Agents ◽

Ductal Adenocarcinoma ◽

Cancer Therapies ◽

Myeloid Derived Suppressor Cells ◽

Tumor Resistance ◽

Cellular Mechanisms ◽

Immunosuppressive Cell

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

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The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression

Vaccines ◽

10.3390/vaccines4040036 ◽

2016 ◽

Vol 4 (4) ◽

pp. 36 ◽

Cited By ~ 109

Author(s):

Viktor Umansky ◽

Carolin Blattner ◽

Christoffer Gebhardt ◽

Jochen Utikal

Keyword(s):

Cancer Progression ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells

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Main Inflammatory Cells and Potentials of Anti-Inflammatory Agents in Prostate Cancer

Cancers ◽

10.3390/cancers11081153 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1153 ◽

Cited By ~ 12

Author(s):

Takuji Hayashi ◽

Kazutoshi Fujita ◽

Makoto Matsushita ◽

Norio Nonomura

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Immune Cells ◽

Acquired Resistance ◽

Suppressor Cells ◽

Basic Research ◽

Inflammatory Cells ◽

Intercellular Signaling ◽

Prostate Cancer Progression ◽

Anti Inflammatory

Prostate cancer is the most common type of cancer and the leading cause of cancer deaths among men in many countries. Preventing progression is a major concern for prostate cancer patients on active surveillance, patients with recurrence after radical therapies, and patients who acquired resistance to systemic therapies. Inflammation, which is induced by various factors such as infection, microbiome, obesity, and a high-fat diet, is the major etiology in the development of prostate cancer. Inflammatory cells play important roles in tumor progression. Various immune cells including tumor-associated neutrophils, tumor-infiltrating macrophages, myeloid-derived suppressor cells, and mast cells promote prostate cancer via various intercellular signaling. Further basic studies examining the relationship between the inflammatory process and prostate cancer progression are warranted. Interventions by medications and diets to control systemic and/or local inflammation might be effective therapies for prostate cancer progression. Epidemiological investigations and basic research using human immune cells or mouse models have revealed that non-steroidal anti-inflammatory drugs, metformin, statins, soy isoflavones, and other diets are potential interventions for preventing progression of prostate cancer by suppressing inflammation. It is essential to evaluate appropriate indications and doses of each drug and diet.

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