scholarly journals Endothelial Stromal PD-L1 (Programmed Death Ligand 1) Modulates CD8 + T-Cell Infiltration After Heart Transplantation

2021 ◽  
Author(s):  
William Bracamonte-Baran ◽  
Nisha A. Gilotra ◽  
Taejoon Won ◽  
Katrina M. Rodriguez ◽  
Monica V. Talor ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
T Cell ◽  
Heart Transplantation ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Hemodynamic Parameters ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death

Background: The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis. Methods: We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection. Results: We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1 + HLA (human leukocyte antigen)-DR + endothelial cells and CD8 + T cells (slope, −18.3 [95% CI, −35.3 to −1.3]; P =0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2 Cre pdl1 fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls. Conclusions: Loss of graft endothelial PD-L1 expression may play a role in regulating CD8 + T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.

scholarly journals Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 57
Author(s):  
Man-Chin Chen ◽  
Christian Ronquillo Pangilinan ◽  
Che-Hsin Lee
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

scholarly journals Predominant donor CD103+CD8+ T cell infiltration into the gut epithelium during acute GvHD: a role of gut lymph nodes

2008 ◽  
Vol 20 (3) ◽  
pp. 385-394 ◽  
Author(s):  
Shu Zhou ◽  
Hisashi Ueta ◽  
Xue-Dong Xu ◽  
Changde Shi ◽  
Kenjiro Matsuno
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Acute Gvhd ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Gut Epithelium

scholarly journals Renal oxidative stress and renal CD8+ T-cell infiltration in mercuric chloride-induced nephropathy in rats: role of angiotensin II

2015 ◽  
Vol 13 (3) ◽  
pp. 324-334 ◽  
Author(s):  
Caterina Peña ◽  
Juan P. Hernández-Fonseca ◽  
Adriana Pedreañez ◽  
Ninoska Viera ◽  
Jesús Mosquera
Keyword(s):  
Oxidative Stress ◽  
T Cell ◽  
Angiotensin Ii ◽  
Mercuric Chloride ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas

Cancer ◽  
2017 ◽  
Vol 123 (17) ◽  
pp. 3291-3304 ◽  
Author(s):  
Seth M. Pollack ◽  
Qianchuan He ◽  
Jennifer H. Yearley ◽  
Ryan Emerson ◽  
Marissa Vignali ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Soft Tissue ◽  
Programmed Cell Death ◽  
Soft Tissue Sarcomas ◽  
Cell Infiltration ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death ◽  
Cell Death Protein

scholarly journals m6A Modification Patterns Identify a Subset of Follicular Lymphoma Harboring an Exhausted Tumor Microenvironment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4486-4486
Author(s):  
Xianhuo Wang ◽  
Tingting Zhang ◽  
Hengqi Liu ◽  
Sicong Zhang ◽  
Kai Fu ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Biological Processes ◽  
T Cell Infiltration ◽  
Cluster A

Abstract Background: Epigenetic dysregulation is important for the pathogenesis of follicular lymphoma (FL). N6-methyladenosine (m6A) is the most common post-transcriptional modification of mRNA. The m6A modification affects a wide range of cellular processes, including RNA stability, export, splicing or translation, and is extensively involved in the development and progression of multiple non-hematological and hematological malignancies. However, the role of m6A modification in FL remain largely unknown. Methods: We comprehensively evaluated the m6A modification patterns of 351 FL patients from three cohorts based on 16 m6A regulators and constructed the m6A gene signature the by unsupervised clustering analysis. The m6A score was then established using principal component analysis. The association between m6A modification patterns and prognostic implications, biological processes, and microenvironment characterizations in FL were further investigated. Results: A total of 16 m6A regulators were finally identified in this study, including 8 writers, 7 readers and one eraser. Two distinct m6A modification patterns, termed as m6A cluster A and m6A cluster B respectively, were identified based on the similarity displayed by the expression levels of 16 m6A regulators and the proportion of ambiguous clustering measure. Patients with m6A cluster A had significantly poorer survival than those with m6A cluster B (p=0.0085) and showed enrichment in cell cycle, DNA replication and mismatch repair biological processes. However, patients with m6A cluster B were markedly enriched in MAPK pathway, WNT pathway, mTOR pathway, natural killer cell mediated cototoxicity, cytokine-cytokine receptor interaction and T-cell receptor pathway. Additionally, myeloid dendritic cell and CD8 + T cell were significantly enriched in m6A cluster A, nevertheless CD4 + T cell was abundant in m6A cluster B. Base on the DEGs between m6A cluster A and m6A cluster B, a m6A gene signature was further constructed, namely m6A gene signature A and m6A gene signature B. Patients with m6A gene signature B experienced worse outcome than those with m6A gene signature A. Simultaneously, a m6A scoring model was also established to quantify the m6A modification pattern of individual patients with FL. Patients with low m6A score presented a prominent inferior survival than those with high m6A score (p< 0.0001). The median survival times for patients with low and high m6A score were 8.84 (95% confidence interval [CI]: 7.251-10.429) and 15.73 years (95% CI: 11.729-19.731), respectively. High m6A score group was remarkably riched in macrophage cell and CD4 + T cell infiltration, while low m6A score group exhibited significantly increased myeloid dendritic cell and CD8 + T cell infiltration, suggesting that m6A score could distinguish populations with distinct immune cell infiltration characteristics. GSVA analysis showed that the expression of genes involved in the immune and inflammatory response was significantly upregulated in low m6A score group. But we finally found that the CD8 + T cells in low m6A score group kept in a state of exhaustion, leading to that exhausted T cells were enriched in low m6A score group. The expression of PD-1 and PD-L1 in low m6A score group was also higher than those in high m6A score group. GSEA analysis showed that low m6A score group exhibited an enhanced IFN-γ response. Finally, we verified the value of the m6A score for predicting response to anti-PD-L1 antibody in external immunotherapy cohort (IMvigor210), and found that patients with low m6A score exhibited significantly clinical benefits and a markedly prolonged survival from anti-PD-L1 therapy. Conclusions: This is the first time to comprehensively investigate the role of m6A modification in FL. The m6A score identifies a subset of follicular lymphoma harboring an exhausted tumor microenvironment and helps for the selection of patients for immunotherapy, guiding the personalized immunotherapy in FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Endothelial Stromal PD-L1 Modulates CD8+ T Cell Infiltration after Heart Transplantation

2021 ◽  
Vol 40 (4) ◽  
pp. S31
Author(s):  
W. Bracamonte-Baran ◽  
N.A. Gilotra ◽  
T. Won ◽  
K.M. Rodriguez ◽  
M. Talor ◽  
...  
Keyword(s):  
T Cell ◽  
Heart Transplantation ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration
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