scholarly journals MicroRNA 21 (miR-21) and miR-181b Couple with NFI-A To Generate Myeloid-Derived Suppressor Cells and Promote Immunosuppression in Late Sepsis

2014 ◽  
Vol 82 (9) ◽  
pp. 3816-3825 ◽  
Author(s):  
Clara McClure ◽  
Laura Brudecki ◽  
Donald A. Ferguson ◽  
Zhi Q. Yao ◽  
Jonathan P. Moorman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cecal Ligation ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Cell Repertoire ◽  
Myeloid Progenitors

ABSTRACTThe sepsis initial hyperinflammatory reaction, if not treated early, shifts to a protracted state of immunosuppression that alters both innate and adaptive immunity and is associated with elevated mortality. Myeloid-derived suppressor cells (MDSCs) are myeloid progenitors and precursors that fail to differentiate into mature innate-immunity cells and are known for their potent immunosuppressive activities. We previously reported that murine MDSCs expand dramatically in the bone marrow during late sepsis, induced by cecal ligation and puncture, and demonstrated that they contribute to late-sepsis immunosuppression. However, the molecular mechanism responsible for generating these immature Gr1+CD11b+myeloid cells during sepsis remains unknown. We show here that sepsis generates a microRNA (miRNA) signature that expands MDSCs. We found that miRNA 21 (miR-21) and miR-181b expression is upregulated in early sepsis and sustained in late sepsis. Importantly, we found that simultaneousin vivoblockade of both miRNAs via antagomiR (a chemically modified miRNA inhibitor) injection after sepsis initiation decreased the bone marrow Gr1+CD11b+myeloid progenitors, improved bacterial clearance, and reduced late-sepsis mortality by 74%. Gr1+CD11b+cells isolated from mice injected with antagomiRs were able to differentiateex vivointo macrophages and dendritic cells and produced smaller amounts of the immunosuppressive interleukin 10 (IL-10) and transforming growth factor β (TGF-β) after stimulation with bacterial lipopolysaccharide, suggesting that immature myeloid cells regained their maturation potential and have lost their immunosuppressive activity. In addition, we found that the protein level of transcription factor NFI-A, which plays a role in myeloid cell differentiation, was increased during sepsis and that antagomiR injection reduced its expression. Moreover, knockdown of NFI-A in the Gr1+CD11b+cells isolated from late-septic mice increased their maturation potential and reduced their production of the immunosuppressive mediators, similar to antagomiR injection. These data support the hypothesis that sepsis reprograms myeloid cells and thus alters the innate immunity cell repertoire to promote immunosuppression, and they demonstrate that this process can be reversed by targeting miR-21 and miR-181b to improve late-sepsis survival.

scholarly journals Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response

2012 ◽  
Vol 80 (6) ◽  
pp. 2026-2034 ◽  
Author(s):  
Laura Brudecki ◽  
Donald A. Ferguson ◽  
Charles E. McCall ◽  
Mohamed El Gazzar
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Cecal Ligation ◽  
Suppressor Cells ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Myeloid Derived Suppressor Cells ◽  
Inflammatory Conditions ◽  
Anti Inflammatory

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are a heterogeneous Gr1+CD11b+population of immature cells containing granulocytic and monocytic progenitors, which expand under nearly all inflammatory conditions and are potent repressors of T-cell responses. Studies of MDSCs during inflammatory responses, including sepsis, suggest they can protect or injure. Here, we investigated MDSCs during early and late sepsis. To do this, we used our published murine model of cecal ligation and puncture (CLP)-induced polymicrobial sepsis, which transitions from an early proinflammatory phase to a late anti-inflammatory and immunosuppressive phase. We confirmed that Gr1+CD11b+MDSCs gradually increase after CLP, reaching ∼88% of the bone marrow myeloid series in late sepsis. Adoptive transfer of early (day 3) MDSCs from septic mice into naive mice after CLP increased proinflammatory cytokine production, decreased peritoneal bacterial growth, and increased early mortality. Conversely, transfer of late (day 12) MDSCs from septic mice had the opposite effects. Early and late MDSCs studiedex vivoalso differed in their inflammatory phenotypes. Early MDSCs expressed nitric oxide and proinflammatory cytokines, whereas late MDSCs expressed arginase activity and anti-inflammatory interleukin 10 (IL-10) and transforming growth factor β (TGF-β). Late MDSCs had more immature CD31+myeloid progenitors and, when treatedex vivowith granulocyte-macrophage colony-stimulating factor (GM-CSF), generated fewer macrophages and dendritic cells than early MDSCs. We conclude that as the sepsis inflammatory process progresses, the heterogeneous MDSCs shift to a more immature state and from being proinflammatory to anti-inflammatory.

IMMU-05. CCR2+ MYELOID-DERIVED SUPPRESSOR CELLS FROM MURINE GLIOMAS ARE SOURCED FROM THE BONE MARROW, SUPPRESS T CELL ACTIVATION, AND MIGRATE TO CCL2

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi92-vi93
Author(s):  
Gregory Takacs ◽  
Christian Kreiger ◽  
Defang Luo ◽  
Joseph Flores-Toro ◽  
Loic Deleyrolle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bone Marrow Cells ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Wild Type ◽  
Suppressive Phenotype

Abstract INTRODUCTION Mounting evidence suggests infiltrating immune-suppressive cells contribute to immune checkpoint inhibitor resistance and poor survival in Glioblastoma (GBM) patients. We have previously shown glioma-associated monocytic-myeloid derived suppressor cells (M-MDSCs) express chemokine receptors CCR2 and CX3CR1. Genetic and pharmacologic targeting of CCR2 promoted sequestration of M-MDSCs in the bone marrow and, in combination with PD-1 blockade, slowed progression of KR158 and 005GSC murine gliomas. This combination treatment also enhanced infiltration of IFNg-producing T cells that were less exhausted. Although CCR2+/CX3CR1+ cells display surface markers indicative of bone marrow-derived M-MDSCs, additional studies are needed to formally establish the source of these cells and to determine if they exhibit an immune-suppressive phenotype as well as migrate to the CCR2 ligands, CCL2 and/or CCL7. OBJECTIVE Evaluate the source, migration, and immune suppressive function of CCR2+/CX3CR1+ myeloid cells from glioma bearing mice. METHODS To identify the source of CCR2+/CX3CR1+ myeloid cells, chimeric wild type mice harboring bone marrow cells from transgenic CCR2WT/RFP/CX3CR1WT/GFP mice were generated. CCR2+/CX3CR1+ cells were enriched from bone marrow obtained from either wild-type or CCR2WT/RFP/CX3CR1WT/GFP naïve and glioma-bearing mice in order to evaluate their immune suppressive phenotype and ability to migrate to CCL2 and CCL7. RESULTS CCR2+/CX3CR1+ cells are present in glioma isolates from chimeric mice, indicative of a bone marrow-derived cell population, and are detectable within the tumor microenvironment as early as 3 days post orthotopic implantation of KR158 cells; these cells accumulate as tumors increase in size (r=0.7605, p=0.007). CCR2+/CX3CR1+ M-MDSCs isolated from the bone marrow of tumor bearing mice suppress CD8+ T cell production of IFNg and migrate to CCL2 more efficiently than CCL7. CONCLUSION CCR2+/CX3CR1+ cells from glioma bearing mice are derived from the bone marrow and represent an immune suppressive population that migrates to CCL2.

scholarly journals Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

2020 ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Age Related ◽  
Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

scholarly journals Calcium/Calmodulin Dependent Protein Kinase Kinase 2 (CaMKK2) Expressed in the Host Promotes Lymphoma Cells Growth By Controlling Myeloid Derived Suppressor Cells Expansion

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 272-272
Author(s):  
Wei Huang ◽  
Yaping Liu ◽  
Nelson J. Chao ◽  
Luigi Racioppi
Keyword(s):  
Conflicts Of Interest ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Luciferase Expression ◽  
Myeloid Derived Suppressor Cells ◽  
Lymphoma Cells ◽  
Hematopoietic Stem ◽  
Calcium Calmodulin Dependent ◽  
Significant Difference ◽  
Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immunosuppressive cells that generate from myeloid progenitors under pathological conditions including cancers.In response to tumor-derived factors, myeloid progenitors differentiate intoimmature myeloid cells and accumulate as monocyte and granulocyte-MDSC (M- and G-MDSC), and correlate with poor survival in patients. Promoting the differentiation of MDSCs towards mature dendritic cells and macrophage is a potential way to eliminate MDSCs and restore anti-tumor immunity. In this study, we demonstrate that the enzyme Calcium/Calmodulin dependent Kinase Kinase 2 (CaMKK2) as a potential therapeutic target to control the growth of lymphoma by regulating the expansion of MDSCs. CaMKK2 is a crucial kinase in the calcium-signaling cascade. Activated by the Ca2+/CaM complex, CaMKK2 can phosphorylate the down stream targets including CaMKI, CaMKIV, and 5' AMP-activated kinase (AMPK). Beyond central nerve system, CaMKK2 is expressed in hematopoietic stem and progenitors cells, and some hematopoietic mature cells including macrophages and monocytes. In adipogenesis, granulopoiesis, and muscle development, CaMKK2 inhibits the differentiation of progenitors towards mature cells. We reasoned that CaMKK2 might have a similar function in myeloid cells, controlling terminal differentiation of tumor-induced MDSCs. We first confirmedthe expression of CaMKK2 in tumor-induced MDSCs. EG.7-OVA lymphoma cells were injected s.c. in the flank of Camkk2-egfp reporter mice, and MDSCs subsets from the tumors and spleens of the mice were assessed by flow cytometry. We found that Camkk2 promoter was highly active in Ly6Chigh/Ly6Gdim subset (M-MDSC), but low in Ly6Cdim/Ly6Ghigh subset (G-MDSC) and Ly6Cneg/Ly6Gneg/F4/80dim/neg/MHC-IIdim/neg cells. (Figure 1) Camkk2 promoter was not active in lymphocytes as previous reported. To determine the function of CaMKK2 expressed in the host, E.G7 cells with luciferase expression were injected into the flank of wild type (WT) and Camkk2-/-mice, and monitored by tumor size and bioluminescent imaging. (Figure 2 A&B) In WT mice injected with E.G7-OVA cells, tumors were detectable by bioluminescence by day 7, and gradually increased in photon signal during the following two weeks. Although tumors successfully engrafted in Camkk2-/-mice, bioluminescent signal gradually decreased after 21 days and eventually disappeared after 32 days. (Figure 2A) In LyM-Cre+Camkk2loxP mice which Camkk2 is selectively deleted in myeloid cell compartment, when challenged with E.G7-OVA cells, similar E.G7 tumor grow suppression was observed as in the Camkk2-/-global knockout model. (Figure 2C) We next demonstrated that Camkk2 deletion decreased MDSCs accumulation in EG7 bearing mice. In normal conditions, Camkk2-/-mice had comparable CD11b+and Ly6ChighLy6Gdim percentage in the spleenswith WT mice, but slightly higher Ly6Cdim Ly6Ghigh percentage. A significant increase of MDSCs percentage was detected in EG.7-bearing mice compared to tumor-free mice; while in Camkk2-/-mice, the MDSC accumulation in E.G7-OVA spleens and tumors showed a significant decrease in percentage compared to WT ones. (Figure 3 A & B) To evaluate whether the failure of MDSC expansion in tumor-bearing Camkk2-/-mice regulated tumor suppression, MDSCs were isolated from the spleens of WT and Camkk2-/-E.G7-OVA-bearing mice, adoptively transferred into Camkk2-/-mice, and followed by tumor inoculation. As expected, lymphoma cells failed to growth in Camkk2-/-control mice without MDSC injection. However, tumors developed in all Camkk2-/-mice that received either WT or Camkk2-/-MDSCs, with no significant difference. (Figure 3C) These results indicated that restoring the number of MDSC was sufficient to revert the protective effect of Camkk2 deletion on tumor growth. Interestingly, this data also suggested that WT and Camkk2-/-MDSCs have a comparable immunosuppressive activity at single-cell level. In conclusion, our results identifies for the first time CaMKK2 as an important component of molecular machinery that mediates the detrimental effect of lymphoma cells on myeloid development. Of note, our data also pinpoint CaMKK2 as a new pharmacological target to limit the expansion of tumor-induced MDSC. Disclosures No relevant conflicts of interest to declare.

scholarly journals Myeloid Cells in Glioblastoma Microenvironment

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 18
Author(s):  
Alessandra De Leo ◽  
Alessio Ugolini ◽  
Filippo Veglia
Keyword(s):  
Bone Marrow ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Primary Brain Tumor ◽  
High Dimensional ◽  
Myeloid Derived Suppressor Cells ◽  
Therapeutic Approaches ◽  
Immune Microenvironment ◽  
Specific Targeting ◽  
Different Populations

Glioblastoma (GBM) is the most aggressive, malignant primary brain tumor in adults. GBM is notoriously resistant to immunotherapy mainly due to its unique immune microenvironment. High dimensional data analysis reveals the extensive heterogeneity of immune components making up the GBM microenvironment. Myeloid cells are the most predominant contributors to the GBM microenvironment; these cells are critical regulators of immune and therapeutic responses to GBM. Here, we will review the most recent advances on the characteristics and functions of different populations of myeloid cells in GBM, including bone marrow-derived macrophages, microglia, myeloid-derived suppressor cells, dendritic cells, and neutrophils. Epigenetic, metabolic, and phenotypic peculiarities of microglia and bone marrow-derived macrophages will also be assessed. The final goal of this review will be to provide new insights into novel therapeutic approaches for specific targeting of myeloid cells to improve the efficacy of current treatments in GBM patients.

scholarly journals Human myeloid-derived suppressor cells derived from the bone marrow maintain their functional ability with aging but have a reduced frequency of induction

2020 ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Myeloid Derived Suppressor Cells ◽  
Age Related ◽  
Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

scholarly journals Human Myeloid-derived Suppressor Cells Derived From the Bone Marrow Are Decreased With Age but Maintain Their Functional Ability

2020 ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Myeloid Derived Suppressor Cells ◽  
Age Related ◽  
Myeloid Progenitors

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known toinhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses onthe role of age-related processes in myelopoiesis.

scholarly journals Swertianolin ameliorates immune dysfunction in sepsis via blocking the immunosuppressive function of myeloid- derived suppressor cells

2021 ◽  
Vol 65 (3) ◽  
Author(s):  
Zongfang Ren ◽  
Haoren Tang ◽  
Linjun Wan ◽  
Xing Liu ◽  
Ning Tang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cecal Ligation ◽  
Cell Activity ◽  
Suppressor Cells ◽  
Interleukin 10 ◽  
Myeloid Derived Suppressor Cells ◽  
Sepsis Model ◽  
Sepsis Induction ◽  
Quality Threshold

In this study, we studied the long-term proliferation trajectory of myeloid-derived suppressor cells (MDSCs) in murine sepsis model and investigated whether swertianolin could modulate the immunosuppressive function of MDSCs. A murine sepsis model was established by cecal ligation and perforation (CLP), according to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. The bone marrow and spleen of the mice were collected at 24 h, 72 h, 7 and 15 d after sepsis induction. The proportions of monocytic-MDSCs (M-MDSCs; CD11b+LY6G-LY6Chi) and granulocytic-MDSCs (G-MDSC, CD11b+ Ly6G+ Ly6Clow) were analyzed by flow cytometry. Then, we have investigated whether swertianolin could modulate the immunosuppressive function of MDSCs in in vitro experiments. G-MDSCs and M-MDSCs increased acutely after sepsis with high levels sustained over a long period of time. G-MDSCs were the main subtype identified in the murine model of sepsis with polymicrobial peritonitis. Furthermore, it was found that swertianolin reduced significantly interleukin-10 (IL-10), nitric oxide (NO), reactive oxygen species (ROS), and arginase production in MDSCs, while reducing MDSC proliferation and promoting MDSC differentiation into dendritic cells. Swertianolin also improved T-cell activity by blocking the immunosuppressive effect of MDSCs. Both subsets of MDSCs significantly increased in the bone marrow and spleen of the mice with sepsis, with G-MDSCs being the main subtype identified. Swertianolin effectively regulated the functions of MDSCs and reduced immune suppression.

scholarly journals Human MDSCs derived from the bone marrow maintain their functional ability but have a reduced frequency of induction in the elderly compared to pediatric donors

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Sara Magri ◽  
Elena Masetto ◽  
Samantha Solito ◽  
Samuela Francescato ◽  
Elisa Belluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Functional Ability ◽  
Ex Vivo ◽  
Suppressor Cells ◽  
The Elderly ◽  
System Level ◽  
Low Grade ◽  
Age Related ◽  
Myeloid Progenitors

AbstractMyeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immunosuppressive cells developing from myeloid progenitors, which are enriched in pathological conditions such as cancer, and are known to inhibit the functions of effector T cells. During aging, several changes occur both at the adaptive and innate immune system level, in a process defined as immunoscenescence. In particular, the low-grade inflammation state observed in the elderly appears to affect hematopoiesis. We previously demonstrated that the combination of GM-CSF and G-CSF drives the in vitro generation of bone marrow-derived MDSCs (BM-MDSCs) from precursors present in human bone marrow aspirates of healthy donors, and that these cells are endowed with a strong immune suppressive ability, resembling that of cancer-associated MDSCs. In the present work we investigated BM-MDSCs induction and functional ability in a cohort of pediatric versus elderly donors. To this aim, we analyzed the differences in maturation stages and ability to suppress T cell proliferation. We found that the ex vivo distribution of myeloid progenitors is similar between pediatric and elderly individuals, whereas after cytokine treatment a significant reduction in the more immature compartment is observed in the elderly. Despite the decreased frequency, BM-MDSCs maintain their suppressive capacity in aged donors. Taken together, these results indicate that in vitro induction of MDSCs from the BM is reduced with aging and opens new hypotheses on the role of age-related processes in myelopoiesis.

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

2017 ◽  
Vol 114 (5) ◽  
pp. 1117-1122 ◽  
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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