PGE2 inhibits natural killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling

Martinet, Ludovic; Jean, Christine; Dietrich, Gilles; Fournié, Jean‐Jacques; Poupot, Rémy

doi:10.1016/j.bcp.2010.05.002

Cited by 108 publications

(81 citation statements)

References 46 publications

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“…37 Martinet and co-workers reported that PGE2 inhibits TCR-activated gd T cell-cytotoxicity by a cAMP-mediated protein kinase A type I-dependent signaling. 26 In addition, EP2-and EP4-specific agonists reduced intracellular IFNg production in activated gd T cells comparable to the addition of exogenous PGE2. 9 An enhanced release of IFNg often leads to reduced intracellular stores of IFNg.…”

Section: E988460-6mentioning

confidence: 92%

“…Similar to the report of Martinet and colleagues, who demonstrated an inhibitory effect of PGE2 on gd T-cell cytotoxicity, we observed that the addition of PGE2 to PDAC cells releasing scarce native PGE2, such as Panc89 and PancTu-I cells, robustly inhibited gd T cell-mediated lysis. 26 In contrast, the addition of exogenous PGE2 to PDAC cells that already released high concentrations of native PGE2 only slightly modulated gd T-cell cytotoxicity, suggesting that the endogenous release of PGE2 by Colo357 cells is sufficient to potently inhibit gd T-cell cytotoxicity. This hypothesis was confirmed by the experiment with the inhibitors Indomethacin and DuP697 that partially abrogated the resistance of Colo357 against gd T-cell mediated lysis.…”

Section: E988460-6mentioning

confidence: 92%

“…9,10 PGE2 binds to prostaglandin E2 and E4 receptors expressed on activated gd T cells, and thereby inhibits T cell receptor (TCR)-activated cytotoxic activity of gd T cells by cyclic adenosine monophosphate (cAMP)-mediated protein kinase A type I-dependent signaling. 26 However, such an enhanced PGE2 synthesis could be potently decreased by the Cox-2 inhibitor celecoxib in a pancreatic cancer xenograft mouse model. 11 Although selective Cox-2 inhibitors such as celecoxib and DuP697 showed anti-proliferative activity toward different tumor entities and against several PDAC cell lines in vitro as well as in vivo, celecoxib as a single agent failed to exert anti-proliferative or antitumor effects toward pancreatic adenocarcinomas resected from patients and implanted in nude mice in a xenograft model, despite a decrease in PGE2 synthesis.…”

Section: Introductionmentioning

confidence: 98%

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Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

Gonnermann

Oberg

Kellner³

et al. 2015

OncoImmunology

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Keywords: Cox-2, cytotoxicity, gammadelta T lymphocytes, human, pancreatic ductal adenocarcinoma, PGE2Abbreviations: BrHPP, bromohydrin-pyrophosphate; Cox, cyclooxygenase; n-BP, nitrogen-containing bisphosphonates; PAg, phosphorylated antigen; PDAC, pancreatic ductal adenocarcinoma; PG, prostaglandins; RTCA, Real Time Cell Analyzer; TCR, T cell receptor.The prostaglandin (PG) synthetase cyclooxygenase 2 (Cox-2) promotes tumorigenesis, tumor progression, and metastasis in a variety of human cancer entities including pancreatic ductal adenocarcinoma (PDAC). In this study, we demonstrate that in PDAC cells such as Colo357 cells, enhanced Cox-2 expression and increased release of the Cox-2 metabolite prostaglandin E2 (PGE2) promotes resistance against gd T cell-mediated lysis. Co-culture with activated gd T cells induced an upregulation of Cox-2 expression in Colo357 cells, and thereby an enhanced PGE2 release, in response to tumor necrosis factor a .TNFa/ secretion from gd T cells. The PGE2-mediated inhibition of gd T cell cytotoxicity against Cox-2-expressing PDAC cells can be partially overcome by Cox-2 inhibitors. Our results show that differences between PDAC cells in regards to sensitivity to gd T-cell cytotoxicity can be due to distinct levels of Cox-2 expression associated with varying amounts of PGE2 release. While gd T cell cytotoxicity against PDAC cells expressing low levels of Cox-2 can be effectively enhanced by tribody [(Her2) 2 £Vg9] with specificity for Vg9 T cell receptor and HER-2/neu on PDAC cells, a combination of tribody [(Her2) 2 £Vg9] and Cox-2 inhibitor is necessary to induce complete lysis of Cox-2 high expressing Colo357. In conclusion, our results suggest that the application of tribody [(Her2) 2 £Vg9] that enhances gd T-cell cytotoxicity and Cox-2 inhibitors that overcome PGE2-mediated resistance of PDAC cells to the cytotoxic activity of gd T cells might offer a promising combined immunotherapy for pancreatic cancer.

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Section: E988460-6mentioning

confidence: 92%

Section: E988460-6mentioning

confidence: 92%

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

Gonnermann

Oberg

Kellner³

et al. 2015

OncoImmunology

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“…Moreover, to our knowledge, this is the first report demonstrating the presence in ovarian cancer-associated ascites of PGE2, which has recently been proposed as a strong inhibitor of Vc9Vd2 T-cell cytotoxicity, in ascitic supernatant. 28 The concentration of PGE2 ranged from 0.03 to 35 ng/ml, and the mean concentration was 10.2 6 15.5 ng/ml (Fig. 4a).…”

Section: Pge2 Is a Primary Contributor To The Immunosuppressive Effecmentioning

confidence: 95%

“…Indeed, studies have shown that ovarian ascites contain well-known immunosuppressive factors, including IL-6, IL-10, TGF-b and VEGF. 26,27 Moreover, recently, Fournie et al 28 have demonstrated that PGE2 inhibits the natural Vc9Vd2 T-cell cytotoxicity triggered by the NKR and TCR through cAMP-mediated PKA Type I-dependent signaling.…”

mentioning

confidence: 99%

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

Lavoué

Cabillic

Toutirais

et al. 2011

Intl Journal of Cancer

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Epithelial ovarian cancer (EOC) usually spreads into the peritoneal cavity, thereby providing an opportunity for intraperitoneal adoptive immunotherapy with Vc9Vd2 T lymphocytes, a T cell subpopulation endowed with high lytic properties against tumor cells. However, previous studies have reported that Vc9Vd2 T cells fail to expand from peripheral blood mononuclear cells in one-third of patients with cancer. Here, from a cohort of 37 patients with EOC, a multiple correspondence analysis identified three populations, one of which was not suitable for Vc9Vd2 T-cell adoptive therapy. Interestingly, the ineligible patients were identified based on the frequency of Vc9Vd2 T cells in their peripheral blood and the patients' age. The average time to tumor recurrence was also found to be significantly different between the three populations, suggesting that the innate immune response is involved in EOC prognosis. A dramatic decrease in the lytic properties of Vc9Vd2 T cells occurred following incubation with ascitic supernatant and was found to be associated with reduced perforin/granzyme degranulation. Prostaglandin E2, but not IL-6, IL-10, VEGF or TGF-b, showed immunosuppressive effects in Vc9Vd2 T cells. Interestingly, our results emphasize that pretreating ovarian tumor cells with zoledronate partially reverses the immunosuppressive effects of ovarian cancer-associated ascites and restores a high level of lytic activity. These data sustain that optimal Vc9Vd2 T-cell adoptive immunotherapy previously requires counteracting the tumor immunosuppressive microenvironment. Altogether, our findings provide a rationale for clinically evaluating Vc9Vd2 T-cell adoptive immunotherapy with intraperitoneal carcinomatosis presensitization by zoledronate in patients with EOC.Epithelial ovarian cancer (EOC) is the fifth most frequent cancer among women and the fourth most common cause of cancer-related deaths among women.1 More than 70% of patients are diagnosed when the cancer has spread beyond the ovaries, and these patients have low median survival rates.2 The prognosis is poor, with a 5-year survival rate of only 30%, and the rate is less than 10% for patients with bulky residual disease remaining after surgery and chemotherapy, which emphasizes the need for innovative treatments.3 The inflammatory microenvironment of ovarian carcinomas prevents the maturation of myeloid cells, favors regulatory T-cell development and restrains the cytotoxic activity of effector T lymphocytes, leading to the escape of the tumor from the immune system. 4 Thus, research is ongoing to develop innovative approaches aimed at stimulating the immune system. 5 The preferential spread pattern of EOC in the peritoneal cavity offers an excellent opportunity for the regional administration of adoptive T-cell therapy.2 Some pilot trials have shown the feasibility of and promising

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The gene expression profile of phosphoantigen‐specific human γδ T lymphocytes is a blend of αβ T‐cell and NK‐cell signatures

et al. 2011

Self Cite

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Global transcriptional technologies have revolutionised the study of lymphoid cell populations, but human cd T lymphocytes specific for phosphoantigens remain far less deeply characterised by these methods despite the great therapeutic potential of these cells. Here we analyse the transcriptome of circulating TCRVc 1 cd T cells isolated from healthy individuals, and their relation with those from other lymphoid cell subsets. We report that the gene signature of phosphoantigen-specific TCRVc 1 cd T cells is a hybrid of those from ab T and NK cells, with more 'NK-cell' genes than ab T cells have and more 'T-cell' genes than NK cells. The expression profile of TCRVc 1 cd T cells stimulated with phosphoantigen recapitulates their immediate physiological functions: Th1 cytokine, chemokine and cytotoxic activities reflect their high mitotic activity at later time points and do not indicate antigen-presenting functions. Finally, such hallmarks make the transcriptome of cd T cells, whether resting or clonally expanding, clearly distinctive from that of NK/T or peripheral T-cell lymphomas of the cd subtype.

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PGE2 inhibits natural killer and γδ T cell cytotoxicity triggered by NKR and TCR through a cAMP-mediated PKA type I-dependent signaling

Cited by 108 publications

References 46 publications

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity

Sensitization of ovarian carcinoma cells with zoledronate restores the cytotoxic capacity of Vγ9Vδ2 T cells impaired by the prostaglandin E2 immunosuppressive factor: Implications for immunotherapy

The gene expression profile of phosphoantigen‐specific human γδ T lymphocytes is a blend of αβ T‐cell and NK‐cell signatures

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