Targeting the dynamic transcriptional landscape of Treg subpopulations in pancreatic ductal adenocarcinoma: Insights from single-cell RNA sequencing analysis with a focus on CTLA4 and TIGIT.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that represents a significant challenge in cancer research and clinical management. In this study, we reanalyzed a published single-cell RNA sequencing (scRNA-seq) dataset from PDAC and adjacent tissues to investigate the heterogeneity of tumor and normal tissue, specifically focusing on the regulatory T cells (Tregs) and their interactions with other cells in the tumor microenvironment (TME). Treg cells were identified and clustered into natural Tregs (nTreg) and induced Tregs (iTreg) based on the expression of specific genes. It was found that the number of iTregs was higher in the tumor than in healthy tissues, while the number of n Tregs was higher in healthy tissues. Differential gene expression analysis was performed, and biological process analysis revealed that the Tregs in PDAC were mostly involved in protein targeting and translation pathways. In addition, ligand-receptor pairs between Tregs and other cell types were identified, and the critical communication pathways between Tregs and endothelial and ductal cells were revealed, which could potentially contribute to the immunosuppressive TME of PDAC. These findings provide insights into the role of Tregs in PDAC and their interactions with other cell types in the TME, highlighting potential targets for immunotherapy, such as the inhibitory immune checkpoint receptors CTLA4 and TIGIT, which are known to be expressed on Tregs and have been shown to play a role in suppressing anti-tumor immune responses.

Immune checkpoint inhibitors and neurotoxicity: a focus on diagnosis and management for a multidisciplinary approach.

INTRODUCTION: Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, the consequential over activation of the immune system is often complicated by adverse events that can affect several organs and systems, including the nervous system. The precise pathophysiology underlying neurological irAEs (n-irAEs) is not completely known. Around 3.8% of patients receiving anti-CTLA-4 agents, 6.1% of patients receiving anti-PD-1/PD-L1, and 12% of patients receiving combination therapies have n-irAEs. Most n-irAEs are low-grade, while severe toxicities have rarely been reported. in this article, we performed an updated literature search on immuno-related neurotoxicity on main medical research database, from February 2017 to December 2023. AREAS COVERED: We have also compared the latest national and international guidelines on n-irAEs management with each other in order to better define patient management. EXPERT OPINION: A multidisciplinary approach appears necessary in the management of oncological patients during immunotherapy. Therefore, in order to better manage these toxicities, we believe that it is essential to collaborate with neurologists specialized in the diagnosis and treatment of n-irAEs, and that a global neurological assessment, both central and peripheral, is necessary before starting immunotherapy, with regular reassessment during treatment.

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Immune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes.

BACKGROUND: Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies. METHODS: This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads. RESULTS: We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival. CONCLUSIONS: Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

Endothelial cells in tumor microenvironment: insights and perspectives.

The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.

Classic pyoderma gangrenosum.

Pyoderma gangrenosum is a rare inflammatory ulcerative skin disease of unknown etiology. We report an image of a patient with pyoderma gangrenosum who presented right leg ulcers with violaceous margins, histologically characterized by mono- and polynuclear cell infiltrates. The patient was successfully treated with cyclosporin A.

Idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH): Similarities, differences and the role of autoimmunity.

Pre-capillary pulmonary arterial hypertension (PAH) is hemodynamically characterized by a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg, pulmonary capillary wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) > 2. PAH is classified in six clinical subgroups, including idiopathic PAH (IPAH) and PAH associated to connective tissue diseases (CTD-PAH), that will be the main object of this review. The aim is to compare these two PAH subgroups in terms of epidemiology, histological and pathogenic findings in an attempt to define disease-specific features, including autoimmunity, that may explain the heterogeneity of response to therapy between IPAH and CTD-PAH.

Predicting Factors of Worse Prognosis in COVID-19: Results from a Cross-sectional Study on 52 Inpatients Admitted to the Internal Medicine Department.

BACKGROUND: The initial phases of the COVID-19 pandemic posed a real need for clinicians to identify patients at risk of poor prognosis as soon as possible after hospital admission. AIM: The study aimed to assess the role of baseline anamnestic information, clinical parameters, instrumental examination, and serum biomarkers in predicting adverse outcomes of COVID-19 in a hospital setting of Internal Medicine. METHODS: Fifty-two inpatients consecutively admitted to the Unit of Internal Medicine "Baccelli," Azienda Ospedaliero - Universitaria Policlinico of Bari (February 1 - May 31, 2021) due to confirmed COVID-19 were grouped into two categories based on the specific outcome: good prognosis (n=44), patients discharged at home after the acute phase of the infection; poor prognosis, a composite outcome of deaths and intensive care requirements (n=8). Data were extracted from medical records of patients who provided written informed consent to participate. RESULTS: The two study groups had similar demographic, anthropometric, clinical, and radiological characteristics. Higher interleukin 6 (IL-6) levels and leucocyte count, and lower free triiodothyronine (fT3) levels were found in patients with poor than those with good prognosis. Higher IL-6 levels and leucocyte count, lower fT3 concentration, and pre-existing hypercholesterolemia were independent risk factors of poor outcomes in our study population. A predicting risk score, built by assigning one point if fT3 < 2 pg/mL, IL-6 >25 pg/mL, and leucocyte count >7,000 n/mm3, revealed that patients totalizing at least 2 points by applying the predicting score had a considerably higher risk of poor prognosis than those with scoring <2 points [OR 24.35 (1.32; 448), p = 0.03]. The weight of pre-existing hypercholesterolemia did not change the risk estimation. CONCLUSION: Four specific baseline variables, one anamnestic (pre-existing hypercholesterolemia) and three laboratory parameters (leucocyte count, IL-6, and fT3), were significantly associated with poor prognosis as independent risk factors. To prevent adverse outcomes, the updated 4-point score could be useful in identifying at-risk patients, highlighting the need for specific trials to estimate the safety and efficacy of targeted treatments.

Adipose failure through adipocyte overload and autoimmunity.

Metabolic syndrome poses a great worldwide threat to the health of the patients. Increased visceral adiposity is recognized as the main determinant of the detrimental clinical effects of insulin resistance. Inflammation and immune system activation in the adipose tissue (AT) have a central role in the pathophysiology of metabolic syndrome, but the mechanisms linking increased adiposity to immunity in the AT remain in part elusive. In this review, we support the central role of adipocyte overload and relative adipose failure as key determinants in triggering immune aggression to AT. This provides a mechanistic explanation of the relative metabolic wellness of metabolically normal obese people and the disruption in insulin signaling in metabolically obese lean people.

Deciphering the immune landscape of head and neck squamous cell carcinoma: A single-cell transcriptomic analysis of regulatory T cell responses to PD-1 blockade therapy.

Immunotherapy is changing the Head and Neck Squamous Cell Carcinoma (HNSCC) landscape and improving outcomes for patients with recurrent or metastatic HNSCC. A deeper understanding of the tumor microenvironment (TME) is required in light of the limitations of patients' responses to immunotherapy. Here, we aimed to examine how Nivolumab affects infiltrating Tregs in the HNSCC TME. We used single-cell RNA sequencing data from eight tissues isolated from four HNSCC donors before and after Nivolumab treatment. Interestingly, the study found that Treg counts and suppressive activity increased following Nivolumab therapy. We also discovered that changes in the CD44-SSP1 axis, NKG2C/D-HLA-E axis, and KRAS signaling may have contributed to the increase in Treg numbers. Furthermore, our study suggests that decreasing the activity of the KRAS and Notch signaling pathways, and increasing FOXP3, CTLA-4, LAG-3, and GZMA expression, may be mechanisms that enhance the killing and suppressive capacity of Tregs. Additionally, the result of pseudo-temporal analysis of the HNSCC TME indicated that after Nivolumab therapy, the expression of certain inhibitory immune checkpoints including TIGIT, ENTPD1, and CD276 and LY9, were decreased in Tregs, while LAG-3 showed an increased expression level. The study also found that Tregs had a dense communication network with cluster two, and that certain ligand-receptor pairs, including SPP1/CD44, HLA-E/KLRC2, HLA-E/KLRK1, ANXA1/FPR3, and CXCL9/FCGR2A, had notable changes after the therapy. These changes in gene expression and cell interactions may have implications for the role of Tregs in the TME and in response to Nivolumab therapy.

Cutaneous polyarteritis nodosa and pulmonary arterial hypertension: An unexpected liaison. A case report.

BACKGROUND: Cutaneous polyarteritis nodosa (cPAN) is a form of medium-sized vessel necrotizing vasculitis. It is a rare, skin-limited variant of polyarteritis nodosa, characterized by dermal and subcutaneous tissue involvement. The most common findings in cPAN include digital gangrene, livedo reticularis, and tender subcutaneous nodules. However, while limited to the skin, cPAN results in significant morbidity and mortality due to the accompanying skin ischemia and necrosis, such that patients are vulnerable to superinfection. Here, we describe a unique presentation of cPAN associated with pulmonary arterial hypertension (PAH). METHODS: A 78-year-old female presented with digital ischemia and leg ulcers associated with PAH. Skin biopsy showed necrotizing fibrinoid necrosis of the small- and middle-sized vessels of the dermis. A diagnosis of cPAN and PAH was made. The patient was treated with glucocorticoids, vasodilators, and cyclophosphamide. RESULTS: She died due to severe sepsis complications. CONCLUSION: To date, this is the first case report describing the association between cPAN and PAH. In this case, PAH is a complication of the cutaneous vasculitides suggesting that vasculopathy could play a role in the pathophysiology of PAH. However, the underlying pathophysiological mechanisms still have to be firmly established.

Corrigendum: Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

[This corrects the article DOI: 10.3389/fcvm.2023.1223660.].

Cancer survivorship at heart: a multidisciplinary cardio-oncology roadmap for healthcare professionals.

In cancer, a patient is considered a survivor from the time of initial diagnosis until the end of life. With improvements in early diagnosis and treatment, the number of cancer survivors (CS) has grown considerably and includes: (1) Patients cured and free from cancer who may be at risk of late-onset cancer therapy-related cardiovascular toxicity (CTR-CVT); (2) Patients with long-term control of not-curable cancers in whom CTR-CVT may need to be addressed. This paper highlights the importance of the cancer care continuum, of a patient-centered approach and of a prevention-oriented policy. The ultimate goal is a personalized care of CS, achievable only through a multidisciplinary-guided survivorship care plan, one that replaces the fragmented management of current healthcare systems. Collaboration between oncologists and cardiologists is the pillar of a framework in which primary care providers and other specialists must be engaged and in which familial, social and environmental factors are also taken into account.

Impact of belimumab therapy on the quality of life in patients with systemic lupus erythematosus: A cohort study.

Systemic lupus erythematosus (SLE) is a chronic and extremely disabling connective-tissue autoimmune disease with a tremendous impact on the quality of life (QoL). Belimumab, a B-lymphocyte-stimulator-specific inhibitor, is the first biologic drug approved as add-on therapy in patients with active, refractory auto-antibody-positive SLE.The impact of belimumab on the QoL of SLE patients was evaluated using a generic questionnaire short-form health survey 36 (SF-36) and the disease-specific questionnaire SLE-specific quality of life (SLEQoL).The Italian version of the SLEQoL and the SF-36 were administered to 46 SLE patients before and after 6 months of belimumab therapy. The control population consisted of 40 age-matched healthy individuals. The questionnaires were completed before and after belimumab treatment and the results were compared using the Wilcoxon signed-rank test. In addition, data from healthy controls and SLE patients were compared using the Mann-Whitney test. Dichotomous variables were compared using Fisher's exact test.For SLE patients, the addition of belimumab to their therapeutic regimen significantly improved their health-related QoL (HRQoL), according to the results of the SF-36 and SLEQoL. The comparison of the data obtained before and after belimumab treatment showed a decrease in all six SLEQoL domains and an increase in all eight SF-36 domains. Moreover, treatment led to a reduction in the median prednisone dose, to 0 mg/day (IQR 0-4.5 mg/day). Before belimumab therapy, SLE patients had a worse HRQoL than the control group, based on both questionnaires, but after belimumab treatment the outcome scores between SLE patients and controls were similar, suggesting that belimumab therapy resulted in a strong improvement in HRQoL. These findings were supported by a decrease in the SELENA-SLEDAI score, a measure of disease activity.In addition to clinical remission and low disease activity, the goals of an innovative therapeutic strategy for SLE should include the attainment of a good HRQoL. Our study demonstrates that the combined use of the SF-36 and SLEQoL questionnaires can provide clinicians with a better understanding of the HRQoL of SLE patients.

Lenalidomide arrests cell cycle and modulates PD1-dependent downstream mTOR intracellular signals in melanoma cells.

Despite numerous efforts to define the best therapeutic strategies in advanced melanoma, the response of many patients remains heterogeneous and of short duration. Lenalidomide, an immunomodulating drug, has shown anti-inflammatory, antiangiogenic and anticancer properties in haematological disorders; however, few preclinical data support the rationale for using this drug in melanoma patients. In this study, we investigate lenalidomide's potential role in melanoma by focusing on the in-vitro drug's antiproliferative activity. The antiproliferative action of lenalidomide was evaluated on two melanoma cell lines by MTT assay, cell cycle and apoptosis assay. P21 protein levels were evaluated with droplet digital PCR (ddPCR) and western blot analysis while his interaction with specific cyclin-dependent kinase (CDK) was assessed by immunoprecipitation test. The biological effect and molecular mechanisms of programmed cell death-1 (PD-1) in the regulation of proliferation were evaluated using ddPCR, flow cytometry, western blot and small interfering RNA transfection. We observed that lenalidomide exerts a cytostatic effect in melanoma cell lines by inducing cell cycle arrest in the G0-G1 phase through p21 upregulation and modulation of CDK complexes. Furthermore, we found that lenalidomide has an antiproliferative action through the downregulation of melanoma-PD1 expression and consequently the alteration of intracellular signaling of mammalian target of rapamycin/S6. The present study aims to provide new insights into the role of lenalidomide in melanoma and suggesting to potentially translating these findings into a clinical setting to use immunomodulatory derivatives for blocking the pro-tumorigenic activity of the melanoma through the PD-1/PD-L1 axis.

Non-Classical HLA Class 1b and Hepatocellular Carcinoma.

A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host's defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.

Single-cell RNA sequencing uncovers heterogeneous transcriptional signatures in tumor-infiltrated dendritic cells in prostate cancer.

Prostate cancer (PCa) is one of the two solid malignancies in which a higher T cell infiltration in the tumor microenvironment (TME) corresponds with a worse prognosis for the tumor. The inability of T cells to eliminate tumor cells despite an increase in their number reinforces the possibility of impaired antigen presentation. In this study, we investigated the TME at single-cell resolution to understand the molecular function and communication of dendritic cells (DCs) (as professional antigen-presenting cells). According to our data, tumor cells stimulate the migration of immature DCs to the tumor site by inducing inflammatory chemokines. Many signaling pathways such as TNF-α/NF-κB, IL2/STAT5, and E2F up-regulated after DCs enter the tumor location. In addition, some molecules such as GPR34 and SLCO2B1 decreased on the surface of DCs. The analysis of molecular and signaling alterations in DCs revealed some suppression mechanisms of tumors, such as removing mature DCs, reducing the DC's survival, inducing anergy or exhaustion in the effector T cells, and enhancing the differentiation of T cells to Th2 and Tregs. In addition, we investigated the cellular and molecular communication between DCs and macrophages in the tumor site and found three molecular pairs including CCR5/CCL5, CD52/SIGLEC10, and HLA-DPB1/TNFSF13B. These molecular pairs are involved in the migration of immature DCs to the TME and disrupt the antigen-presenting function of DCs. Furthermore, we presented new therapeutic targets by the construction of a gene co-expression network. These data increase our knowledge of the heterogeneity and the role of DCs in PCa TME.

Early and Late Response and Glucocorticoid-Sparing Effect of Belimumab in Patients with Systemic Lupus Erythematosus with Joint and Skin Manifestations: Results from the Belimumab in Real Life Setting Study-Joint and Skin (BeRLiSS-JS).

AIM: To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. METHODS: All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (<2.6) and LDA (≥2.6, ≤3.2), CLASI = 0, 1, and improvement in DAS28 and CLASI indices ≥20%, ≥50%, and ≥70% were evaluated at 6, 12, 24, and 36 months. RESULTS: DAS28 < 2.6 was achieved by 46%, 57%, and 71% of patients at 6, 12, and 24 months, respectively. CLASI = 0 was achieved by 36%, 48%, and 62% of patients at 6, 12, and 24 months, respectively. Belimumab showed a glucocorticoid-sparing effect, being glucocorticoid-free at 8.5%, 15.4%, 25.6%, and 31.6% of patients at 6, 12, 24, and 36 months, respectively. Patients achieving DAS-LDA and CLASI-50 at 6 months had a higher probability of remission at 12 months compared with those who did not (p = 0.034 and p = 0.028, respectively). CONCLUSIONS: Belimumab led to clinical improvement in a significant proportion of patients with joint or skin involvement in a real-life setting and was associated with a glucocorticoid-sparing effect. A significant proportion of patients with a partial response at 6 months achieved remission later on during follow-up.

The emerging role of noncoding RNAs in systemic lupus erythematosus: new insights into the master regulators of disease pathogenesis.

Auto-immune diseases are a form of chronic disorders in which the immune system destroys the body's cells due to a loss of tolerance to self-antigens. Systemic lupus erythematosus (SLE), identified by the production of autoantibodies in different body parts, is one of the most well-known examples of these diseases. Although the etiology of SLE is unclear, the disease's progression may be affected by genetic and environmental factors. As studies in twins provide adequate evidence for genetic involvement in the SLE, other phenomena such as metallization, histone modifications, and alterations in the expression of noncoding RNAs (ncRNAs) also indicate the involvement of epigenetic factors in this disease. Among all the epigenetic alterations, ncRNAs appear to have the most crucial contribution to the pathogenesis of SLE. The ncRNAs' length and size are divided into three main classes: micro RNAs, long noncoding RNAs (LncRNA), and circular RNAs (circRNAs). Accumulating evidence suggests that dysregulations in these ncRNAs contributed to the pathogenesis of SLE. Hence, clarifying the function of these groups of ncRNAs in the pathophysiology of SLE provides a deeper understanding of the disease. It also opens up new opportunities to develop targeted therapies for this disease.

Unraveling the Role of Peroxisome Proliferator-Activated Receptor ß/Δ (PPAR ß/Δ) in Angiogenesis Associated with Multiple Myeloma.

Growing evidence suggests a role for peroxisome proliferator-activated receptor ß/δ (PPAR ß/δ) in the angiogenesis, growth, and metastasis of solid tumors, but little is known about its role in multiple myeloma (MM). Angiogenesis in the bone marrow (BM) is characteristic of disease transition from monoclonal gammopathy of undetermined significance (MGUS) to MM. We examined the expression and function of PPAR ß/δ in endothelial cells (EC) from the BM of MGUS (MGEC) and MM (MMEC) patients and showed that PPAR ß/δ was expressed at higher levels in MMEC than in MGEC and that the overexpression depended on myeloma plasma cells. The interaction between myeloma plasma cells and MMEC promoted the release of the PPAR ß/δ ligand prostaglandin I2 (PGI2) by MMEC, leading to the activation of PPAR ß/δ. We also demonstrated that PPAR ß/δ was a strong stimulator of angiogenesis in vitro and that PPAR ß/δ inhibition by a specific antagonist greatly impaired the angiogenic functions of MMEC. These findings define PGI2-PPAR ß/δ signaling in EC as a potential target of anti-angiogenic therapy. They also sustain the use of PPAR ß/δ inhibitors in association with conventional drugs as a new therapeutic approach in MM.