Search

IL‐10, produced by a wide variety of cells, is a highly pleiotropic cytokine that plays a critical role in the control of immune responses. However, its regulatory activity in tumor immunity remains poorly understood. In this study, we report that IL‐10 deficiency robustly suppressed the formation of malignant pleural effusion (MPE) and significantly enhanced miR‐7116‐5p expression in pleural CD4+ T cells. We demonstrated that miR‐7116‐5p suppressed IL‐10‐mediated MPE formation by inhibiting pleural vascular permeability as well as tumor angiogenesis and tumor growth. IL‐10 promoted MPE formation by suppressing miR‐7116‐5p that enhances TH1 response. We identified G protein‐coupled receptor 55 (GPR55) as a potential target of miR‐7116‐5p, and miR‐7116‐5p promoted TH1 cell function by downregulating GPR55. Moreover, GPR55 promoted MPE formation by inhibiting TH1 cell expansion through the ERK phosphorylation pathway. These results uncover an IL‐10‐mediated pathway controlling TH1 cells and demonstrate a central role for miR‐7116‐5p/GPR55/ERK signaling in the physiological regulation of IL‐10‐driven pro‐malignant responses. [ABSTRACT FROM AUTHOR]

Background: The objective of our study was to analyze the prognostic value of the combination of serum ALP and pleural effusion LDH (AL score) for malignant pleural effusion (MPE) patients. Methods: This study includes retrospective, descriptive and observational research from 1 June 2006 to 1 December 2017, which aimed to identify prognostic factors related to MPE patients. We analyzed the association of various clinical features, routinely tested markers from peripheral blood and MPE at diagnosis and overall survival (OS). All MPE patients were assigned to three groups according to their AL score. The impact of the AL score and other prognostic factors were evaluated with multivariable regression. Results: According to their AL score, 193 patients were assigned to three groups with 25 in group 0 (sALP < 65 U/L and pLDH < 155 U/L), 121 in group 1 (sALP > 65 U/L or pLDH > 155 U/L) and 47 (sALP > 65 U/L and pLDH > 155 U/L) in group 2. For groups 0, 1 and 2, median survival times (MST) were 23, 15 and 7 months, respectively. Among the three groups, MST, serum albumin level, C reactive protein, erythrocyte sedimentation rate, the ratios of platelet‐to‐lymphocyte, neutrophil‐to‐lymphocyte showed significant differences. The counts of neutrophils, monocytes, platelets and AL score (0 vs. 1, P = 0.038, hazard ratio [HR]: 1.858, 95% confidence interval [CI]: [1.034, 3.339]; 0 vs. 2, P = 0.001, HR: 2.993, 95% CI: [1.556, 5.531]) were independent prognostic indicators for OS of MPE patients. Conclusion: AL score is a promising indicator which can be used to predict the prognosis of MPE patients. It can assist physicians in the selection of patients for appropriate palliative treatment. Key points: To our knowledge, this paper is the first study that combined two enzymes (sALP and pLDH) from serum and pleural effusion and studied the prognostic value for MPE patients. It has been proved to be a promising indicator to assist physicians select patients for appropriate palliative treatment. [ABSTRACT FROM AUTHOR]

The role of IL‐10 in malignant pleural effusion (MPE) remains unknown. By using murine MPE models, we observed that an increase in pleural IL‐10 was a significant predictor of increased risk of death. We noted that TH1‐ and TH17‐cell content in MPE was higher in IL‐10–/– mice than in WT mice, and IL‐10 deficiency promoted differentiation into TH1 but not into TH17 cells. A higher fraction of TH1 and TH17 cells in the MPE of IL‐10–/– mice expressed CXCR3 compared with WT mice. We also demonstrated that Lewis lung cancer and colon adenocarcinoma cells secreted large amounts of CXCL10, a ligand of CXCR3, which induced the migration of TH1 and TH17 cells into the MPE, and IFN‐γ could promote this signaling cascade. Furthermore, intrapleural injection of mice with CXCL10‐deficient tumor cells led to decreased TH1‐ and TH17‐cell content in MPE, increased MPE volume, and reduced survival of MPE‐bearing mice. Taken together, we demonstrated that IL‐10 deficiency promoted T‐cell differentiation into TH1 cells and upregulated the CXCR3‐CXCL10 signaling pathway that recruits TH1 and TH17 cells into MPE, ultimately resulting in decreased MPE formation and longer survival time of mice‐bearing MPE. IL‐10 promoted the development of malignant pleural effusion by suppressing the differentiation of naïve CD4+ T cells into TH1 cells and by suppressing the CXCR3‐CXCL10 signal that traffics TH1 and TH17 cells into the pleural space. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that Myo9b is a cancer metastasis-related protein and functions in a variety of immune-related diseases. However, it is not clear whether and how Myo9b functions in malignant pleural effusion (MPE). In this study, our data showed that Myo9b expression levels correlated with lung cancer pleural metastasis, and nucleated cells in MPE from either patients or mice expressed a lower level of Myo9b than those in the corresponding blood. Myo9b deficiency in cancer cells suppressed MPE development via inhibition of migration. Myo9b deficiency in mice suppressed MPE development by decreasing T H 1 cells and increasing T H 17 cells. CD4 + naive T cells isolated from Myo9b -/- mouse spleens exhibited less T H 1 cell differentiation and more T H 17 cell differentiation in vitro. mRNA sequencing of nucleated cells showed that T cell-specific adaptor protein (TSAd) was downregulated in Myo9b -/- mouse MPE, and enrichment of the H3K27me3 mark in the TSAd promoter region was found in the Myo9b -/- group. Naive T cells purified from wild type mouse spleens transfected with TSAd-specific small interfering RNAs (siRNAs) also showed less T H 1 cell differentiation and more T H 17 cell differentiation than those from the siRNA control group. Furthermore, downregulation of TSAd in mice using cholesterol-conjugated TSAd-specific siRNA suppressed MPE development, decreased T H 1 cells, and increased T H 17 cells in MPE in vivo. Taken together, Myo9b deficiency suppresses MPE development not only by suppressing pleural cancer metastasis but also by regulating T H 1/T H 17 cell response via a TSAd-dependent pathway. This work suggests Myo9b and TSAd as novel candidates for future basic and clinical investigations of cancer., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Inflammatory signaling networks between tumor cells and immune cells contribute to the development of malignant pleural effusion (MPE). B cells have been found in MPE; however, little is known about their roles there. In the present study, by using mouse MPE models, we noted that although the total B cells in MPE were decreased as compared with the corresponding blood and spleen, the percentage of activated naïve B cells expressing higher levels of CD80, CD86, myosin heavy chain-II, CD44, CD69, and programmed cell death-ligand 1 (PD-L1) molecules were increased in wild-type mouse MPE. Compared with wild-type mice, decreased T helper (T H )1 cells and increased T H 17 cells were present in B cell-deficient mouse MPE, which paralleled to the reduced MPE volume and longer survival time. Adoptive transfer of activated naïve B cells into B cell-deficient mice was able to increase T H 1 cells and decrease T H 17 cells in MPE and shorten the survival of mice bearing MPE. Furthermore, we demonstrated that activated naïve B cells inhibited T H 17-cell expansion via the PD-1/PD-L1 pathway and promoted naïve CD4 + T-cell differentiation into T H 1/T H 17 cells through secreting IL-27/IL-6 independent of the PD-1/PD-L1 pathway. Collectively, our data uncovered a mechanism by which naïve B cells promote MPE formation by regulating T H 1/T H 17 cell responses, making these B cells an attractive target for therapeutic intervention in the fight against cancer.