scholarly journals Low CD8+ T Cell Infiltration and High PD-L1 Expression Are Associated with Level of CD44+/CD133+ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 541 ◽  
Author(s):  
Ya-Chin Hou ◽  
Ying-Jui Chao ◽  
Min-Hua Hsieh ◽  
Hui-Ling Tung ◽  
Hao-Chen Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
T Cells ◽  
Cancer Stem Cells ◽  
Cd8 T Cells ◽  
Death Receptor ◽  
Recurrence Risk ◽  
Immune Checkpoints ◽  
Prognostic Effect ◽  
A Minor

Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effects to evade immune system recognition. However, the clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, high infiltration of CD8+ T cells could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.

scholarly journals Low CD8+ T Cell Infiltration and High PD-L1 Expression Are Associated with CD44+/CD133+ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer

2019 ◽  
Author(s):  
Ya-Chin Hou ◽  
Ying-Jui Chao ◽  
Min-Hua Hsieh ◽  
Hui-Ling Tung ◽  
Hao-Chen Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
T Cells ◽  
Cancer Stem Cells ◽  
Cd8 T Cells ◽  
Death Receptor ◽  
Recurrence Risk ◽  
Immune Checkpoints ◽  
Immune Recognition ◽  
Prognostic Effect

Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effect to evade the immune recognition. However, clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, CD8+ T cells infiltration could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.

scholarly journals Immunomodulatory Molecules On Lung Cancer Stem Cells From Lymph Nodes Aspirates

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 838
Author(s):  
Agata Raniszewska ◽  
Iwona Kwiecień ◽  
Rafał Sokołowski ◽  
Elżbieta Rutkowska ◽  
Joanna Domagała-Kulawik
Keyword(s):  
Lung Cancer ◽  
Stem Cells ◽  
T Cells ◽  
Cancer Stem Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Checkpoint Inhibitors ◽  
Lymphocyte Subpopulation ◽  
Endobronchial Ultrasound ◽  
Multiparameter Flow Cytometry

Over the past decade, immune checkpoint inhibitors have revolutionized the treatment of non-small cell lung cancer (NSCLC). Unfortunately, not all patients benefit from PD-(L)1 blockade, yet, the PD-L1 tumor cell expression is the only approved biomarker, and other biomarkers have been investigated. In the present study, we analyzed the presence of immunomodulatory molecules: PD-L1, CD47, CD73, Fas, and FasL on mature tumor cells (MTCs) and cancer stem cells (CSCs) in lymph nodes (LNs) aspirates and refer it to the lymphocyte subpopulation in peripheral blood (PB). PB samples and LNs aspirates obtained during the endobronchial ultrasound-guided transbronchial needle aspiration (EBUS/TBNA) procedure of 20 patients at different stages of NSCLC. The cells were analyzed by multiparameter flow cytometry. We reported the higher frequency of MTCs and CSCs expressing the investigated immunomodulating molecules in metastatic LNs than in nonmetastatic. The expression of CD47 and PD-L1 was significantly higher on CSCs than on MTCs. Among the lymphocyte subpopulation in PB, we observed a higher frequency of PD-1+ CD8 T cells and Fas+ CD8 T cells in patients with confirmed metastases than in nonmetastatic. Next, we found that the percentage of FasL+ MTCs correlated with the frequency of Fas+ CD3 T cells in LNs aspirates and Fas+ CD8 T cells in PB. Finally, we found that patients with metastatic disease had a significantly higher FasL+/Fas+ MTCs ratio than patients with nonmetastatic disease. Both MTCs and CSCs express different immunomodulatory molecules on their surface. The frequency of FasL+ MTCs associates with altered distribution of Fas+ lymphocyte subpopulations in LNs and PB.

Vector Prime-Protein Boost Vaccine Induces 20 Fold Decrease in the Levels of CD44+CD24−/Low Cancer Stem Cells in Epithelial Neoplasms

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2908-2908
Author(s):  
Yucheng Tang ◽  
Hakan Akbulut ◽  
Jonathan Maynard ◽  
Pingchaun Li ◽  
Albert B. Deisseroth
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Cancer Stem Cells ◽  
Cd8 T Cells ◽  
Carcinoma Cells ◽  
Older Individuals ◽  
Tumor Stem Cells ◽  
Vaccine Platform ◽  
Protein Boost ◽  
Boost Vaccine

Abstract Since a significant portion (30%) of individuals diagnosed with epithelial neoplasms have highly chemotherapy resistant CD44+CD24−/low cancer stem cells in the peripheral blood as well as in solid tumor nodules at diagnosis, we have been developing methods of cancer treatment which depend on methods of killing the cancer stem cells which depend on mechanisms other than chemotherapy for treatment. Vaccination has been one of these approaches. Unfortunately, it has been known for a long time that the immune response is diminished in older individuals due to decreased numbers of CD4 and CD8 T cells and due to acquisition of functional defects in CD4 cells. An example is the diminished expression of the CD40L in activated CD4 T cells in older individuals which limits the cellular and humoral response to vaccines in the older age groups. The presence of the CD40L on the CD4 helper T cells is important for vaccine induced expansion of antigen specific T cells and B cells. In order to overcome these problems, we have developed an Ad-sig-TAA/ecdCD40L vector prime-TAA/ecdCD40L protein boost vaccine strategy. The Ad-sig-TAA/ecdCD40L carries a transcription unit encoding the extracellular domain (ecd) of the CD40 ligand (CD40L) linked to tumor associated antigen (TAA). The TAA are in turn linked to a secretory signal peptide (sig) so that the TAA/ecdCD40L protein will be secreted from the vector infected cells at the injection site of the vector continuously over a 10–14 day period. The CD40L targets the TAA to the DCs, activates the DCs, and carries the TAA into the DC so that the TAA fragments are presented on Class I MHC. The sc injection of the TAA/ecdCD40L protein booster following the sc administration of the Ad-sig-TAA/ecdCD40L (we call this the TAA/ecdCD40L VPP vaccine) induces complete regressions of pre-existing tumor even in aged mice (18 months old). We then chose human MUC-1 as the TAA for testing the efficacy of our vaccine platform for cancer stem cells. Over 90% of the late stage patients with cancers of the breast, ovary, prostate, and lung have been reported to overexpress a hypoglycosylated form of MUC-1 which correlates with decreased time to progression. The hypoglycosylation on MUC-1 in cancer cells creates a tumor specific target for vaccines. Kufe’s lab has shown that overexpression of MUC-1 in the cancer cell promotes resistance to therapy by reducing p53 (Cancer Cell7: 167, 2005) and induces proliferation by activation of the NFkappaB (Nature Cell Biology9: 1419, 2007). Finn’s lab has shown that MUC-1 is a marker present on >90% of the “tumor stem cell” population as well as the more mature cells in breast cancer (Ca Res68: 2419, 2008). In order to test the efficacy of the hMUC-1/ecdCD40L VPP vaccine on tumor stem cells, we first isolated hMUC-1 positive Lewis Lung carcinoma cells by stably transfecting the hMUC-1 cDNA into these cells. We showed that the Ad-sig-hMUC-1/ecdCD40L vector prime-hMUC-1/ecdCD40L protein boost vaccine overcomes anergy to hMUC-1 antigen (hMUC-1) in hMUC-1.Tg mice. We then injected 100,000 human MUC- 1 positive Lewis Lung mouse carcinoma cells (LL2/LL1hMUC-1) mouse cancer cells into the syngeneic C57BL/6J mice. ELISPOT assay showed that the hMUC-1/ecdCD40L VPP vaccine increased the level of antigen specific CD8 effector cells in the lymph node draining the site of injection of the tumor to 900 hMUC-1 specific CD8 T cells/100,000 total cells and to 325 hMUC-1 specific CD8 T cells/100,000 cells in the spleen. The level of cytotoxicity of spleen cells increased 6 fold following vaccination (spleen cells from control and vaccinated mice were exposed in vitro to mitomycin C treated hMUC positive LL2/LL1hMUC-1 cells for 5 days before testing). Measurement of the growth of the sc tumor nodule at the sc injection site showed a 20 fold decrease in the total size of the tumor in the vaccinated vs the control mice and the size of the tumor was decreasing in the vaccinated mice vs the control group at the time of sacrifice at 24 days. Finally, the tumor nodule from the vaccinated and unvaccinated mice were excised post mortem, minced, treated with collagenase and DNAse I and strained through gauze. FACS analysis showed that in the vaccinated mice, the number of the MUC-1 positive tumor stem cells with the CD44+CD24− immunophenotype decreased over 20 fold during the treatment period. These results suggest that the hMUC-1/ecdCD40L VPP vaccine could suppress the levels of hMUC-1 cancer stem cells in pre-existing tumor nodules. This vaccine platform has entered clinical phase I testing.

270 Inhibition of FLIP Renders Pancreatic Cancer Stem Cells Susceptible to Death Receptor-Mediated Apoptosis

2010 ◽  
Vol 138 (5) ◽  
pp. S-50
Author(s):  
Ryan Herde ◽  
Courtney L. Scaife ◽  
Phillip D. Gray ◽  
Scott K. Kuwada
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Death Receptor ◽  
Pancreatic Cancer Stem Cells

Molecular Mechanisms Underlying the Functions of Cellular Markers Associated with the Phenotype of Cancer Stem Cells

2019 ◽  
Vol 14 (5) ◽  
pp. 405-420 ◽  
Author(s):  
Eduardo Alvarado-Ortiz ◽  
Miguel Á. Sarabia-Sánchez ◽  
Alejandro García-Carrancá
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Molecular Mechanisms ◽  
Tumor Biology ◽  
Molecular Tools ◽  
Recent Past ◽  
Functional Roles ◽  
Cellular Population ◽  
Cellular Markers ◽  
A Minor

Cancer Stem Cells (CSC) generally constitute a minor cellular population within tumors that exhibits some capacities of normal Stem Cells (SC). The existence of CSC, able to self-renew and differentiate, influences central aspects of tumor biology, in part because they can continue tumor growth, give rise to metastasis, and acquire drug and radioresistance, which open new avenues for therapeutics. It is well known that SC constantly interacts with their niche, which includes mesenchymal cells, extracellular ligands, and the Extra Cellular Matrix (ECM). These interactions regularly lead to homeostasis and maintenance of SC characteristics. However, the exact participation of each of these components for CSC maintenance is not clear, as they appear to be context- or cell-specific. In the recent past, surface cellular markers have been fundamental molecular tools for identifying CSC and distinguishing them from other tumor cells. Importantly, some of these cellular markers have been shown to possess functional roles that affect central aspects of CSC. Likewise, some of these markers can participate in regulating the interaction of CSC with their niche, particularly the ECM. We focused this review on the molecular mechanisms of surface cellular markers commonly employed to identify CSC, highlighting the signaling pathways and mechanisms involved in CSC-ECM interactions, through each of the cellular markers commonly used in the study of CSC, such as CD44, CD133, CD49f, CD24, CXCR4, and LGR5. Their presence does not necessarily implicate them in CSC biology.

scholarly journals Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

2021 ◽  
Author(s):  
L. Sams ◽  
S. Kruger ◽  
V. Heinemann ◽  
D. Bararia ◽  
S. Haebe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Prognostic Information ◽  
Peripheral Blood Mononuclear

Abstract Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

scholarly journals Integrated lipidomics and proteomics reveal cardiolipin alterations, upregulation of HADHA and long chain fatty acids in pancreatic cancer stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claudia Di Carlo ◽  
Bebiana C. Sousa ◽  
Marcello Manfredi ◽  
Jessica Brandi ◽  
Elisa Dalla Pozza ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Fatty Acid ◽  
Cancer Stem Cells ◽  
Acyl Chain ◽  
Fatty Acid Elongase ◽  
Acyl Chains ◽  
A Chain ◽  
Pancreatic Cancer Stem Cells ◽  
Long Chain

AbstractPancreatic cancer stem cells (PCSCs) play a key role in the aggressiveness of pancreatic ductal adenocarcinomas (PDAC); however, little is known about their signaling and metabolic pathways. Here we show that PCSCs have specific and common proteome and lipidome modulations. PCSCs displayed downregulation of lactate dehydrogenase A chain, and upregulation of trifunctional enzyme subunit alpha. The upregulated proteins of PCSCs are mainly involved in fatty acid (FA) elongation and biosynthesis of unsaturated FAs. Accordingly, lipidomics reveals an increase in long and very long-chain unsaturated FAs, which are products of fatty acid elongase-5 predicted as a key gene. Moreover, lipidomics showed the induction in PCSCs of molecular species of cardiolipin with mixed incorporation of 16:0, 18:1, and 18:2 acyl chains. Our data indicate a crucial role of FA elongation and alteration in cardiolipin acyl chain composition in PCSCs, representing attractive therapeutic targets in PDAC.

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