Indomethacin-mediated enhancement of lymphocyte response to mitogens in healthy subjects and lung cancer patients

Han, Tao; Takita, Hiroshi

doi:10.1002/1097-0142(19801201)46:11<2416::aid-cncr2820461120>3.0.co;2-g

Cited by 32 publications

(4 citation statements)

References 11 publications

(3 reference statements)

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“…Previous studies demonstrated that normal human monocytes suppressed either the phytohemagglutinin (PHA) or antigen-induced lymphocytes proliferative response when the monocyte-lymphocyte ratio was increased [50]. Also, human monocytes could be stimulated to secrete large amounts of prostaglandins in vitro , which have been shown to inhibit mitogen-induced lymphocyte response, resulting in suppressing the anti-cancer immunity in various cancers [51], [52], [53]. Therefore, these might be the possible explanations that either an elevated lymphocyte count or depressed monocyte count was favorable prognostic predictor in NPC patients.…”

Section: Discussionmentioning

confidence: 99%

A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma

et al. 2013

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BackgroundNasopharyngeal carcinoma (NPC) is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20–30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients.MethodsA retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival (LRRFS), respectively.ResultsUnivariate analysis revealed that higher LMR level (≥5.220) was significantly associated with superior OS, DFS and DMFS (P values <0.001). The higher lymphocyte count (≥2.145×109/L) was significantly associated with better OS (P = 0.002) and DMFS (P = 0.031), respectively, while the lower monocyte count (<0.475×109/L) was associated with better OS (P = 0.012), DFS (P = 0.011) and DMFS (P = 0.003), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR = 0.558, 95% confidence interval or 95% CI = 0.417–0.748; P<0.001), DFS (HR = 0.669, 95% CI = 0.535–0.838; P<0.001) and DMFS (HR = 0.543, 95% CI = 0.403–0.732; P<0.001), respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053) and DMFS (P = 0.080).ConclusionsThe elevated pretreatment peripheral LMR level was a significant favorable factor for NPC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of NPC patients.

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Section: Discussionmentioning

confidence: 99%

A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma

et al. 2013

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“…High levels of PGE2 have been shown to suppress immune surveillance (181)(182)(183) and to impair killing of malignant cells (184,185). These effects appear to be specific to PGE2 since other eicosanoids have not been shown to have a clear role in the regulation of cellular and humoral immune responses (186).…”

Section: Immune Modulationmentioning

confidence: 99%

“…In support of a suppressive effect of PGE2 is the observation that drugs that inhibit PG synthesis enhance immune responses (184)(185)(186). PGE2 can regulate immune function by acting as a negative feedback inhibitor for such processes as T cell proliferation, lymphokine production and cytotoxicity and for macrophage and natural killer cell cytotoxicity (183,187). Since the growth of various tumors is associated with immune suppression in animals and humans (181,188), inhibition of COX may reduce tumorigenesis.…”

Section: Immune Modulationmentioning

confidence: 99%

Prostaglandins and cancer

Fischer

1997

Front Biosci

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Prostaglandins (PGs) are lipids produced enzymatically and nonenzymatically from 20 carbon fatty acids, particularly arachidonic acid. Prostaglandins and related metabolites (collectively referred to as eicosanoids), including the thromboxanes, prostacyclins, hydroperoxy and hydroxy fatty acids, and leukotrienes are produced by most tissues of the body by oxidation of arachidonic acid, although the amount and class of product varies with cell type. The biological action of many of these eicosanoids as key regulators of cell processes that range from proliferation to adhesion and migration are currently being elucidated. An association of high levels of PGs and their synthetic enzymes, the PG synthases/cyclooxygenases, have been noted for many of the major types of cancer. Prostaglandins may contribute to the cancer processes through one or more of several mechanisms including increased proliferation, apoptosis, enhanced carcinogen metabolism or modulation of the immune system. The recent understanding of the regulation of substrate availability and of the regulation (or dysregulation in many neoplasias) of the synthetic enzymes has opened avenues leading to the design of isozyme specific inhibitors and better cancer prevention strategies. However, the apoptosis caused by these inhibitors as well as other drugs has raised some question concerning the relative importance of PGs. This is an issue that remains to be resolved.

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“…46 Indomethacin was also found to improve T-cell cell responses to antigen stimulation in patient with melanoma or lung cancer. 47,48 Studies by Lang et al, have shown that use of the selective Cox-2 inhibitor, Rofecoxib, improved monocyte migration and function to levels seen in healthy controls. 49 Other studies have shown that use of selective Cox-2 inhibitors as chemopreventative agents reduces the expansion of immature myeloid suppressor cells.…”

Section: Discussionmentioning

confidence: 99%

Tumor Secretion of VEGF Induces Endothelial Cells to Suppress T cell Functions Through the Production of PGE2

Mulligan¹,

Rosenzweig²,

Young³

2010

Journal of Immunotherapy

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Summary Endothelial cells are potent regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. Previous studies by our laboratory showed that exposure to Lewis lung carcinoma (LLC)-secreted products induced endothelial cells to suppress T-cell functions in vitro. The current studies examined in vitro and in vivo the mechanism by which tumors induce the formation of suppressor endothelial cells and the means by which suppressor endothelial cells disrupt T-cell functions. In vitro studies demonstrated that inhibition of tumor-derived VEGF with neutralizing antibodies or treatment of endothelial cells with the VEGF receptor tyrosine kinase inhibitor, SU5416, prevented endothelial cells from being induced to suppress T-cell functions. Treatment of tumor-bearing mice with SU5416 blocked the development of endothelial cells that are suppressive to CD4+ and CD8+ T-cell functions. We next examined the role of suppressor endothelial cell-derived PGE2 in the inhibition of T-cell functions. Abrogation of endothelial cell PGE2 production in vitro with indomethacin prevented tumor-conditioned media from stimulating endothelial cell production of immune inhibitory activity toward T-cell functions. Similar treatment of endothelial cells from lungs of tumor-bearing mice blocked their capacity to produce T-cell-inhibitory mediators. These studies demonstrate that tumor-derived VEGF induces endothelial cells to upregulate production of PGE2 which, in turn, leads to suppression of T-cell functions.

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Indomethacin-mediated enhancement of lymphocyte response to mitogens in healthy subjects and lung cancer patients

Cited by 32 publications

References 11 publications

A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma

A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma

Prostaglandins and cancer

Tumor Secretion of VEGF Induces Endothelial Cells to Suppress T cell Functions Through the Production of PGE2

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