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 B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

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 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 MRI of tumor T cell infiltration in response to checkpoint inhibitor therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000328 ◽  
Author(s):  
Xiaoyu Jiang ◽  
Stephanie Dudzinski ◽  
Kathryn E Beckermann ◽  
Kirsten Young ◽  
Eliot McKinley ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cell Size ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Response Criteria ◽  
Non Invasive ◽  
T Cell Infiltration

BackgroundImmune checkpoint inhibitors, the most widespread class of immunotherapies, have demonstrated unique response patterns that are not always adequately captured by traditional response criteria such as the Response Evaluation Criteria in Solid Tumors or even immune-specific response criteria. These response metrics rely on monitoring tumor growth, but an increase in tumor size and/or appearance after starting immunotherapy does not always represent tumor progression, but also can be a result of T cell infiltration and thus positive treatment response. Therefore, non-invasive and longitudinal monitoring of T cell infiltration are needed to assess the effects of immunotherapies such as checkpoint inhibitors. Here, we proposed an innovative concept that a sufficiently large influx of tumor infiltrating T cells, which have a smaller diameter than cancer cells, will change the diameter distribution and decrease the average size of cells within a volume to a degree that can be quantified by non-invasive MRI.MethodsWe validated our hypothesis by studying tumor response to combination immune-checkpoint blockade (ICB) of anti-PD-1 and anti-CTLA4 in a mouse model of colon adenocarcinoma (MC38). The response was monitored longitudinally using Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED), a diffusion MRI-based method which has been previously shown to non-invasively map changes in intracellular structure and cell sizes with the spatial resolution of MRI, in cell cultures and in animal models. Tumors were collected for immunohistochemical and flow cytometry analyzes immediately after the last imaging session.ResultsImmunohistochemical analysis revealed that increased T cell infiltration of the tumors results in a decrease in mean cell size (eg, a 10% increase of CD3+ T cell fraction results a ~1 µm decrease in the mean cell size). IMPULSED showed that the ICB responders, mice with tumor volumes were less than 250 mm3 or had tumors with stable or decreased volumes, had significantly smaller mean cell sizes than both Control IgG-treated tumors and ICB non-responder tumors.ConclusionsIMPULSED-derived cell size could potentially serve as an imaging marker for differentiating responsive and non-responsive tumors after checkpoint inhibitor therapies, a current clinical challenge that is not solved by simply monitoring tumor growth.

scholarly journals Risk Signature Related to Immunotherapy Reaction of Hepatocellular Carcinoma Based on the Immune-Related Genes Associated With CD8+ T Cell Infiltration

2021 ◽  
Vol 8 ◽  
Author(s):  
Yiping Zou ◽  
Zhihong Chen ◽  
Hongwei Han ◽  
Shiye Ruan ◽  
Liang Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Risk Group ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Immune Related Genes

Background: Hepatocellular carcinoma (HCC) is the most common histological type of liver cancer, with an unsatisfactory long-term survival rate. Despite immune checkpoint inhibitors for HCC have got glories in recent clinical trials, the relatively low response rate is still a thorny problem. Therefore, there is an urgent need to screen biomarkers of HCC to predict the prognosis and efficacy of immunotherapy.Methods: Gene expression profiles of HCC were retrieved from TCGA, GEO, and ICGC databases while the immune-related genes (IRGs) were retrieved from the ImmPort database. CIBERSORT and WGCNA algorithms were combined to identify the gene module most related to CD8+ T cells in the GEO cohort. Subsequently, the genes in hub modules were subjected to univariate, LASSO, and multivariate Cox regression analyses in the TCGA cohort to develop a risk signature. Afterward, the accuracy of the risk signature was validated by the ICGC cohort, and its relationships with CD8+ T cell infiltration and PDL1 expression were explored.Results: Nine IRGs were finally incorporated into a risk signature. Patients in the high-risk group had a poorer prognosis than those in the low-risk group. Confirmed by TCGA and ICGC cohorts, the risk signature possessed a relatively high accuracy. Additionally, the risk signature was demonstrated as an independent prognostic factor and closely related to the CD8+ T cell infiltration and PDL1 expression.Conclusion: A risk signature was constructed to predict the prognosis of HCC patients and detect patients who may have a higher positive response rate to immune checkpoint inhibitors.

scholarly journals Induction of T-Cell Infiltration and Programmed Death Ligand 2 Expression by Adeno-Associated Virus in Rhesus Macaque Skeletal Muscle and Modulation by Prednisone

2017 ◽  
Vol 28 (6) ◽  
pp. 493-509 ◽  
Author(s):  
Megan L. Cramer ◽  
Guohong Shao ◽  
Louise R. Rodino-Klapac ◽  
Louis G. Chicoine ◽  
Paul T. Martin
Keyword(s):  
Skeletal Muscle ◽  
T Cell ◽  
Rhesus Macaque ◽  
Cell Infiltration ◽  
Adeno Associated Virus ◽  
T Cell Infiltration ◽  
Programmed Death

Co-inhibition of the TGF-β pathway and the PD-L1 checkpoint by pH-responsive clustered nanoparticles for pancreatic cancer microenvironment regulation and anti-tumor immunotherapy

2020 ◽  
Vol 8 (18) ◽  
pp. 5121-5132 ◽  
Author(s):  
Yang Wang ◽  
Zhuxin Gao ◽  
Xiaojiao Du ◽  
Senbiao Chen ◽  
Wangcheng Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
Tumor Cells ◽  
Tumor Immunotherapy ◽  
Cell Infiltration ◽  
Cancer Microenvironment ◽  
Ph Responsive ◽  
T Cell Infiltration

LYiClustersiPD-L1 could deliver LY2157299 to PSCs and release PAMAM/siPD-L1 to penetrate into tumors and target tumor cells. On synergistic therapy of both, enhanced CD8+ T cell infiltration and cytotoxicity were expected.

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