Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Breser, María Laura; Motrich, Rubén Darío; Sánchez, Leonardo R.; Mackern-Oberti, Juan Pablo; Rivero, Virginia

doi:10.4049/jimmunol.1202482

Cited by 48 publications

(125 citation statements)

References 48 publications

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“…Microarray studies showed that Ccl5 and Cxcl9 / 10 were the only T cell chemokines induced after romidepsin treatment (Table S2). To examine whether T cell recruitment was necessary for the anti-tumor effect of romidepsin, we pre-treated mice with TAK-779, an inhibitor of CCR5 and CXCR3 (26), the receptors of CCL5 and Cxcl9 / 10/11 , respectively. TAK-779 prevented the romidepsin-induced increase in T cell density (CD4: 1.4% to 0.9% and CD8: 2.7% to 1.2%), but did not reduce steady state T cell numbers (CD4: 0.6% to 0.8% and CD8: 0.9 to 1.0%) (Fig.…”

Section: Resultsmentioning

confidence: 99%

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

Zheng

Zhao

Yan

et al. 2016

Clinical Cancer Research

284

219

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Purpose A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g. ~20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies which increase T cell infiltration to tumors can be efficacious in enhancing immunotherapy response. Experimental Design We performed an unbiased screen to identify FDA-approved oncology agents with ability to enhance T cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms. Results We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T cell chemokines in cancer cells, macrophages and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T cell infiltration, and T cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor-infiltrating T cells. Conclusions These results provide evidence for a novel role of HDACs in modulating T cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacological induction of T cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment.

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Section: Resultsmentioning

confidence: 99%

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

Zheng

Zhao

Yan

et al. 2016

Clinical Cancer Research

284

219

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“…88 Prostate inflammation has also been examined histologically, 3 with data to show increased leukocyte infiltration and increased numbers of T cells (more specifically, CD8 + T cells) compared with controls. 89 …”

Section: Cytokine and Chemokine Associationmentioning

confidence: 99%

Immune mediators of chronic pelvic pain syndrome

2014

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The cause of chronic pelvic pain syndrome (CPPS) has yet to be established. Since the late 1980s, cytokine, chemokine, and immunological classification studies using human samples have focused on identifying biomarkers for CPPS, but no diagnostically beneficial biomarkers have been identified, and these studies have done little to deepen our understanding of the mechanisms underlying chronic prostatic pain. Given the large number of men thought to be affected by this condition and the ineffective nature of current treatments, there is a pressing need to elucidate these mechanisms. Prostatitis types IIIa and IIIb are classified according to the presence of pain without concurrent presence of bacteria; however, it is becoming more evident that, although levels of bacteria are not directly associated with levels of pain, the presence of bacteria might act as the initiating factor that drives primary activation of mast-cell-mediated inflammation in the prostate. Mast cell activation is also known to suppress regulatory T cell (Treg) control of self-tolerance and also activate neural sensitization. This combination of established autoimmunity coupled with peripheral and central neural sensitization can result in the development of multiple symptoms, including pelvic pain and bladder irritation. Identifying these mechanisms as central mediators in CPPS offers new insight into the prospective treatment of the disease.

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“…It has been indicated the levels of IFN-γ, TNF-α and IL-1β were elevated in the semen of CP / CPPS-suffering patients [20]. IFN-γ/STAT1 signaling pathway has also been shown plays an important role in the immune responses to prostatitis in experimental autoimmune prostatitis mouse model [21]. However the researches about whether the testosterone reduces the prostatitis and the regulated mechanism relate to IFN-γ/STAT1 signaling pathway both remain lacked.…”

Section: Introductionmentioning

confidence: 99%

Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway

Fan

et al. 2017

PLoS ONE

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Prostatitis is a common condition in adult men of all ages. Uropathogenic Escherichia coli (UPEC) are most frequent pathogen involved in bacterial prostatitis by refluxing the infected urine into prostatic ducts and resulting in an ascending urethral infection. However, the study about the mechanisms of UPEC to invade, replicate and persist in normal prostate epithelial cell is only few. Given the fact that UPEC is pathogen most frequently involved in prostatitis and that testosterone has been demonstrated to attenuate prostate inflammation caused by other etiologies. In this study we investigated whether the testosterone reduces the prostatitis and related mechanism by regulating IFN-γ/STAT1 signaling pathway. In the current study aimed to clarify whether testosterone influences the process of UPEC-induced prostate inflammation and invasion into the prostate epithelial cells. In addition, we set up a normal prostate cell model for UPEC infection to evaluate the ability to invade the urothelial cells as well as the colonization of intercellular bacterial communities in vitro. By using the model, we examine the effects of testosterone to suppress effectively the invasion and survival of UPEC in the prostate cells, and inhibit LPS-induced inflammatory responses through the JAK/STAT1 pathway have also been indicated. Our results demonstrated testosterone not only suppressed the invasion and colonization of UPEC, but also inhibited the expression of pro-inflammatory IL-1β, IL-6 and IL-8 cytokines expression induced by UPEC in a dose-dependent manner. We found the effective dose of testosterone to suppress UPEC infect prostate cells may be appropriate under 40μg/ml. Our data also revealed 20μg/ml testosterone treated PZ-HPV-7 cells significantly suppressed the LPS-induced JAK/STAT1 pathway and inflammatory responses, and reached to maximal effects at 40μg/ml treatment. These results indicate that testosterone plays an anti-inflammatory role in LPS-induced prostate cell inflammation by down-regulating JAK/STAT1 signaling pathway. Interestingly, the JAK inhibitor and testosterone for 24hr pretreatment rather markedly induced the colonization of UPEC in the PZ-HPV-7 cells. Based on the above data, the suppression of UPEC colonization in the prostate cells by testosterone seems to be unrelated with JAK/STAT signaling pathway, whereas the JAK may involve into the UPEC infection. Summing up these data, our findings have demonstrated the suppressive effects of testosterone on the invasion and survival of UPEC and induced inflammation in prostate epithelial cells. These findings indicate the action mechanism of testosterone as an anti-inflammatory mediator in the prostate cells is regulated through JAK/STAT1 signaling pathway, may be beneficial in treating prostate inflammation. Altogether, this study has provided the possibility that using testosterone in the prevention and clinical treatment of prostatitis is a new direction.

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Expression of CXCR3 on Specific T Cells Is Essential for Homing to the Prostate Gland in an Experimental Model of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

Cited by 48 publications

References 48 publications

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma

Immune mediators of chronic pelvic pain syndrome

Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway

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