scholarly journals Key Markers Involved in the Anticolon Cancer Response of CD8+ T Cells through the Regulation of Cholesterol Metabolism

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Liang Dong ◽  
Xi Yang ◽  
Yangyanqiu Wang ◽  
Yin Jin ◽  
Qing Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Network Analysis ◽  
Gene Family ◽  
Cd8 T Cells ◽  
Cholesterol Metabolism ◽  
Differential Expression Analysis ◽  
High Expression ◽  
Ppi Network ◽  
Low Expression

Background. T cell-mediated antitumor immune response is the basis of colorectal cancer (CRC) immunotherapy. Cholesterol plays an important role in T cell signal transduction and function. Apolipoprotein E (APOE) plays a major role in cholesterol metabolism. Objective. To screen and analyze key markers involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism. Methods. Based on the median cutoff of the expression value of APOE according to the data downloaded from The Cancer Genome Atlas and Gene Expression Omnibus database, patients were grouped into low and high expression groups. Differences in clinical factors were assessed, and survival analysis was performed. Differentially expressed genes (DEGs) in the high and low expression groups were screened, followed by the analysis of differences in tumor-infiltrating immune cells and weighted gene coexpression network analysis results. The closely related genes to APOE were identified, followed by enrichment analysis, protein–protein interaction (PPI) network analysis, and differential expression analysis. Immunohistochemical staining (IHC) was used to detect the expression of CD8 in CRC tissues. Results. There were significant differences in prognosis and pathologic_N between the APOE low and high expression groups. A total of 2,349 DEGs between the high and low expression groups were selected. A total of 967 genes were obtained from the blue and brown modules. The probability of distribution of CD8+ T cells differed significantly between the two groups, and 320 closely related DEGs of APOE were screened. Genes including the HLA gene family, B2M, IRF4, and STAT5A had a higher degree in the PPI network. GEO datasets verified the prognosis and the related DEGs of APOE. IHC staining verified the relationship between the distribution of CD8+ T cells and APOE expression. Conclusion. Genes including the HLA gene family, B2M, IRF4, and STAT5A might be the key genes involved in the anticolon cancer response of CD8+ T cells through the regulation of cholesterol metabolism.

Mutated Nucleophosmin 1 (NPM1) Is an Immunogenic Target and Patients with NPM1mut Acute Myeloid Leukemia (AML) Showed High Expression of Different Leukemia-Associated Antigens (LAAs)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3592-3592
Author(s):  
Susanne Hofmann ◽  
Vanessa Schneider ◽  
Lars Bullinger ◽  
Yoko Ono ◽  
Anita Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Microarray Analysis ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
High Expression ◽  
Chromium Release ◽  
Cell Responses ◽  
Favorable Prognosis

Abstract Abstract 3592 Nucleophosmin gene 1 mutations (NPM1mut) are one of the most frequent molecular alterations in AML and distinct immune responses might contribute to the favorable prognosis of AML patients with NPM1mut. Recently, we showed specific T cell responses of CD4+ and CD8+ T cells against epitopes derived from mutated regions of NPM1 (Greiner et al., Blood. 2012 May 16, Epub). In the present study, we investigated clinical parameters and the clinical outcome of NPM1mut AML patients in accordance to their immune responses against different NPM1 epitopes. Moreover, we examined the quantitative expression of different leukemia-associated antigens (LAAs) in NPM1mutAML patients. In ELISpot analysis of 33 healthy volunteers and 27 AML patients, we detected T cell responses of CD4+ and CD8+ T cells against epitopes derived from the mutated region of NPM1. We performed further tetramer assays against the most interesting epitopes and chromium release assays to show the cytotoxicity of peptide-specific T cells. Microarray analysis was performed to analyze the expression of different LAAs in NPM1mut and NPM1wtAML patients. Two epitopes (peptide #1 and #3) derived from NPM1mut induced CD8+ T cell responses. 33% of the NPM1mut AML patients showed immune responses against peptide #1 and 44% against peptide #3. NPM1mut AML patients showed a significantly higher frequency of T cell responses against peptide #3 in contrast to HVs (p=0.046), whereas for peptide #1 the frequency of T cell responses of AML NPM1mut patients and HVs was not significantly different. Specific lysis of pulsed T2 cells but also NPM1mut leukemic blasts was detected in chromium release assays. Therefore, overlapping peptides (OL) were analyzed in ELISpot assays and the peptide called OL8 showed favorable results to activate both CD8+ and CD4+ T cells. We performed survival analysis for these 33 NPM1mut patients analyzed by ELISpot comparing cases with or without specific T cell responses. Our data suggest a trend to a better overall survival (OS) for patients with specific T cell responses against peptide #1 or #3. However, the patient numbers are small and the data have to be interpreted carefully. Analyses with material from larger controlled clinical trials with a high number of patients with NPM1mut AML have to be performed. Our microarray analysis of 30 AML patients showed a high expression of different LAAs like RHAMM, WT-1 and BCL-2 in all subtypes of cells of NPM1mutAML patients, also in leukemic progenitor cells. This demonstrates that NPM1 is an AML subtype suitable for poly-targeted immunotherapeutic trials. Taken together, NPM1mut might constitute an interesting target structure for individualized immunotherapeutic approaches in NPM1mut AML patients. We hypothesize that immune responses to NPM1 mutation may contribute to the favorable prognosis. Disclosures: No relevant conflicts of interest to declare.

A novel method to identify and monitor endogenous tumor-reactive T cells by high expression of CD11a (LFA-1) and PD-1 (CD279) as immunologic readout for evaluating the efficacy of PD-1 blockade.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3037-3037
Author(s):  
Haidong Dong ◽  
Svetomir Markovic ◽  
Christopher J Krco ◽  
Eugene D. Kwon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Stage Iv ◽  
High Expression ◽  
Mouse Tumor ◽  
Cytotoxic Lymphocytes ◽  
Phenotypic Analysis ◽  
Activated T Cells ◽  
Cell Immunity

3037 Background: Tumor immunotherapies directed towards enhancing natural or endogenous anti-tumor T-cell immunity in patients with advanced malignancies are currently being implemented in clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, a reliable T-cell marker is needed. Methods: We utilized CD11a (LFA-1, lymphocyte functional-associated antigen 1), an integrin up-regulated on effector and memory CD8 T-cells, and PD-1 (programmed death-1), an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantitate and monitor endogenous tumor-reactive cytotoxic lymphocytes (CTLs) in two mouse tumor models and the peripheral blood (PB) of 12 patients with stage IV melanoma. Results: High expression of CD11a and PD-1 was identified among CD8 T-cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the PB of melanoma patients, tumor antigen-specific CD8 T cells were associated with a population of CD11a high CD8 T-cells which co-expressed high levels of PD-1, as opposed to eleven healthy donors who had a much lower frequency of PD-1+ CD11a high CD8 T-cells (p <0.0001). Phenotypic analysis showed that CD11a high CD8 T-cells are proliferating (Ki67 positive) activated (CD62L low, CD69 high) T-cells. Increased CD11a high CD8 T-cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector function of CD8 T cells is compromised by co-expression of elevated levels of PD-1. Conclusions: CD11a high CD8 T-cell population expresses high levels of PD-1 and is likely the cellular target of PD-1 blockade therapy. High expression of CD11a (LFA-1) and PD-1 (CD279) by CD8 T-cells may represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of therapy, but also contribute to the selection of patients with solid malignancies likely to benefit from anti-PD-1 therapy.

scholarly journals Prognostic significance of SDF-1 in colorectal cancer depends on CD8+ T-cell density

2020 ◽  
Author(s):  
Alexandros Lalos ◽  
Ali Tülek ◽  
Nadia Tosti ◽  
Robert Mechera ◽  
Alexander Wilhelm ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Cell Density ◽  
Cd8 T Cells ◽  
Prognostic Significance ◽  
Cd8 T Cell ◽  
High Expression ◽  
Prognostic Impact

Abstract Background: Since colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T cells are associated with improved disease-free and overall survival in colorectal cancer (CRC). Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on colorectal cancer (CRC). However, based on a significant correlation of SDF-1 and CD8+ T cells in a previous study (r=0.53, p<0.0001), we hypothesized that the prognostic significance of SDF-1 in CRC could depend on the immune microenvironment. Therefore, we explored the combined prognostic significance of SDF-1 expression and CD8+ T cell density in a large CRC collective. Methods: We analyzed a tissue microarray (TMA) of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells (TICs) and CD8+ T-cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort (TCGA). Results: We found that the the combined high expression of SDF-1 and CD8+ T-cell infiltration shows a favorable 5-year overall survival rate (66%; 95%CI=48–79%) compared to tumors showing a high expression of CD8+ T-cells only (55%; 95%CI=45–64%; p=0.0004). High expression of SDF-1 and CD8+ T-cells infiltration was significantly associated with a favorable prognosis also in a validation group (p=0.016). Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T cells was an independent, favorable, prognostic marker for overall survival (HR=0.34, 95%CI=0.17–0.66; p=0.002 and HR=0.45, 95%CI=0.23–0.89; p=0.021, respectively). In a spearman’s correlation analysis from the TCGA cohort, SDF-1 also correlated significantly with CD8+ T cells (r=0.28). Conclusions: SDF-1 high /CD8 high density represents an independent, favorable, prognostic condition in CRC, most likely due to an effective antigen-specific immune response.

“Immunophenotype Signature of CD8 + T Cells Indicates Impaired Development of a CD26high Memory Subset On Imatinib treatment”.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1650-1650
Author(s):  
Kazuaki Yokoyama ◽  
Arinobu Tojo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
High Expression ◽  
Control Group ◽  
Facs Analysis ◽  
Cd26 Expression ◽  
Memory Subset

Abstract Abstract 1650 Poster Board I-676 CD26 is a kind of T cell costimulatory molecule with dipeptidyl peptidase IV activity in its extracellular domain. Based on the expression level of CD26, CD4+ and CD8+ T cells can be divided into 3 (high/int/low) subsets (Figure 1A). The significance of CD26 has been studied mainly on CD4+ T cells, and CD26highCD4+ T cells are considered to represent memory T cells with typical Th1 responses. Furthermore, we reported a significant decrease in number of this subset in CML patients under imatinib (IM) therapy compared with those under IFNa therapy as well as normal volunteers (control). The role of each subset of CD8+ T cells remains to be elucidated. By analogy to a CD4+CD26high subset, we hypothesized that CD8+CD26high cells might represent a memory subset which could be affected by IM treatment. To test this notion, we first tried to define each CD8+ subset based on its expression of 13 well-known surface antigens by multi-parameter flow cytometry (FACS) analysis. FACS data for each CD8+CD26 subset from control group (n=20) were subjected to the unsupervised hierarchical clustering analysis. As a result, the hierarchical clustering revealed three major clusters (cluster I, II and III; Figure1B), which consisted of 20, 26 and 14 data respectively. Cluster I is characterized by high expression of CD127, CD28, CCR5 and CD45RO (a memory profile), to which all 20 data from high subset were categorized. Cluster II is characterized by high expression of CD27, CD62L, CCR7 and CD45RA (a naive profile), to which all 20 data from int subset and 6 of 20 data from low subset were categorized. Cluster III is characterized by high expression of IFNg, perfolin, granzymeB, CD57 and CD11a (a differentiated effector profile), to which 14 of 20 data from low subset was categorized. Thus, we could categorize CD8+ T cells according to the level of CD26 expression. We next investigated the effects of IM on these 3 distinct subsets in CD8+ T cell differentiation program. Then, we compared immunophenotype signature of each CD8+ CD26 subset between IM group and control group (population frequency among CD8+ T cells, absolute cell count and surface antigen profile). We observed a significant decrease of CD8+CD26high subset in IM group (Figure1C), compared with control group. Altered phenotypic profile (decreased CD127/CD28 expression) was also noted in this subset from IM group (Figure1D). Finally, we investigated the impact of IM on primed CD8+ T cells in vitro. Peripheral blood CD8+ T cells were purified from normal subjects, primed with various stimuli and subjected to the grading doses of IM, followed by FACS analysis. CFSE labeling was used for monitoring cell proliferation. Stimuli included anti-CD3/CD28 MAb (aCD3), common g-chain cytokines (IL-7, IL-15), and their combination. Half inhibitory concentrations (IC50) of IM with 95% confidence interval were also calculated (Figure 1E). We found that CD8+ T cells in the presence of therapeutic concentrations of IM showed a reduced activation status (as determined by up-regulation of CD26 expression) and impaired proliferation (as determined by CFSE intensity) in response to TCR engagement as well as cytokine stimulation. Our present results not only propose a potential utility of CD26 as a convenient marker for functional (naïve/memory/effector) compartments of CD8+ T cells, but also offer another evidence for immunomodulatory effects of IM or the significant role of Abl (-related) kinase in memory CD8+ T cell development, possibly in common g-chain cytokine(s)-dependent manner. Disclosures No relevant conflicts of interest to declare.

CD8 T cells are not required for islet destruction induced by a CD4+ islet-specific T-cell clone

Diabetes ◽  
1992 ◽  
Vol 41 (12) ◽  
pp. 1603-1608 ◽  
Author(s):  
B. J. Bradley ◽  
K. Haskins ◽  
F. G. La Rosa ◽  
K. J. Lafferty
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Clone ◽  
T Cell Clone
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