Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages

Chêne, Anne-Claire; D'Almeida, Sènan Mickael; Blondy, Thibaut; Tabiasco, Julie; Deshayes, Sophie; Fonteneau, Jean-François; Cellerin, L.; Delneste, Yves; Grégoire, Marc; Blanquart, Christophe

doi:10.1016/j.jtho.2016.06.022

Cited by 69 publications

(73 citation statements)

References 27 publications

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“…[3][4][5][6][7][8][9] Several cytokines accumulated in the pleural effusion of MPM patients promote the M2 polarization of macrophages. 10,11 M2/M3-macrophages and Gr-MDSC of MPM patients, as well as MPM cells reduce the proliferation of heterologous CD8a molecule-positive (CD8 þ ) T lymphocytes, by producing immunosuppressive mediators such as reactive oxygen species (ROS), nitric oxide (NO) and kynurenine. 3,4,7,10,[12][13][14] MDSCs are killed by active CD8 þ T lymphocytes, whereas either Tregs and MDSCs reduce CD8 þ T lymphocyte activity and memory CD8 þ T lymphocyte recruitment, inducing a vicious immunosuppressive circle.…”

Section: Introductionmentioning

confidence: 99%

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Salaroglio

Kopecka

Napoli³

et al. 2019

Journal of Thoracic Oncology

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Introduction: A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified. Methods:We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome.Results: The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule-positive (CD4 þ ) programmed death 1-positive (PD-1 þ ) (>5.2%) and CD8 þ PD-1 þ (6.4%) cells, CD4 þ lymphocyte activating 3-positive (LAG-3 þ ) (>2.8% ) and CD8 þ LAG-3 þ (>2.8%) cells, CD4 þ T cell immunoglobulin and mucin domain 3positive (TIM-3 þ ) (>2.5%), and CD8 þ TIM-3 þ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes.

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Section: Introductionmentioning

confidence: 99%

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Salaroglio

Kopecka

Napoli³

et al. 2019

Journal of Thoracic Oncology

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“…These events trigger a long-lasting inflammation, which can enhance DNA damage for the production of free radicals and inflammatory cytokines [9]. The long-lasting inflammation caused by MM and the poor response to therapeutics might be due to the ability of MM cells to subvert host immune response [10, 11]. The knowledge of MM pathophysiology might influence MM patients therapy and survival [4, 12–14].…”

Section: Introductionmentioning

confidence: 99%

Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line

et al. 2017

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Malignant mesothelioma (MM) is a primary tumor arising from the serous membranes. The resistance of MM patients to conventional therapies, and the poor patients’ survival, encouraged the identification of molecular targets for MM treatment. Curcumin (CUR) is a “multifunctional drug”. We explored the in vitro effects of CUR on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, autophagy of human (MM-B1, H-Meso-1, MM-F1), and mouse (#40a) MM cells. In addition, we evaluated the in vivo anti-tumor activities of CUR in C57BL/6 mice intraperitoneally transplanted with #40a cells forming ascites.CUR in vitro inhibited MM cells survival in a dose- and time-dependent manner and increased reactive oxygen species’intracellular production and induced DNA damage. CUR triggered autophagic flux, but the process was then blocked and was coincident with caspase 8 activation which activates apoptosis. CUR-mediated apoptosis was supported by the increase of Bax/Bcl-2 ratio, increase of p53 expression, activation of caspase 9, cleavage of PARP-1, increase of the percentage of cells in the sub G1 phase which was reduced (MM-F1 and #40a) or abolished (MM-B1 and H-Meso-1) after MM cells incubation with the apoptosis inhibitor Z-VAD-FMK. CUR treatment stimulated the phosphorylation of ERK1/2 and p38 MAPK, inhibited that of p54 JNK and AKT, increased c-Jun expression and phosphorylation and prevented NF-κB nuclear translocation. Intraperitoneal administration of CUR increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM treatment using CUR.

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“…19 It has been demonstrated that pleural effusions from MM patients induce recruitment of monocytes and influence their differentiation into M2 macrophages. 20 These macrophages promote the development and metastatic capacity of tumors due to the production of protumor factors like the enzyme arginase 1,21 and a larger M2 component of the total macrophage count is inversely correlated with survival. [22][23][24] The role of galectin-9 in MM remains uncharacterized.…”

Section: Introductionmentioning

confidence: 99%

Targeting the C-terminus of galectin-9 induces mesothelioma apoptosis and M2 macrophage depletion

et al. 2019

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Galectin-9 has emerged as a promising biological target for cancer immunotherapy due to its role as a regulator of macrophage and T-cell differentiation. In addition, its expression in tumor cells modulates tumor cell adhesion, metastasis, and apoptosis. Malignant mesothelioma (MM) is an aggressive neoplasm of the mesothelial cells lining the pleural and peritoneal cavities, and in this study, we found that both human MM tissues and mouse MM cells express high levels of galectin-9. Using a novel monoclonal antibody (mAb) (Clone P4D2) that binds the C-terminal carbohydrate recognition domain (CRD) of galectin-9, we demonstrate unique agonistic properties resulting in MM cell apoptosis. Furthermore, the P4D2 mAb reduced tumor-associated macrophages differentiation toward a protumor phenotype. Importantly, these effects exerted by the P4D2 mAb were observed in both human and mouse in vitro experiments and not observed with another antigalectin-9 specific mAb (clone P1D9) that engages the N-terminus CRD of galectin-9. In syngeneic murine models of MM, P4D2 mAb treatment inhibited tumor growth and improved survival, with tumors from P4D2-treated mice exhibited reduced infiltration of tumor-associated M2 macrophages. This was consistent with an increased production of inducible nitric oxide synthase, which is a major enzyme-regulating macrophage inflammatory response to cancer. These data suggest that using an antigalectin 9 mAb with agonistic properties similar to those exerted by galectin-9 may provide a novel multitargeted strategy for the treatment of mesothelioma and possibly other galectin-9 expressing tumors. ARTICLE HISTORY

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Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages

Cited by 69 publications

References 27 publications

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma

Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line

Targeting the C-terminus of galectin-9 induces mesothelioma apoptosis and M2 macrophage depletion

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