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.

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 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.

Overexpression of LILRB2 (ILT4) is correlated with immunosuppressive immune infiltration in lung adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20519-e20519
Author(s):  
Butuo Li ◽  
Chao Jiang ◽  
Shijiang Wang ◽  
Xuanzong Li ◽  
Yiyue Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Objective Response ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
M2 Macrophage ◽  
Immune Infiltration ◽  
T Cell Infiltration ◽  
The Relationship

e20519 Background: Immune checkpoint inhibitors have revolutionized the patterns of tumor treatment with significantly improved survival. However, it’s worth noting that the objective response rate of PD-1/PD-L1 inhibitors monotherapy is just 20% in non-small cell lung cancer (NSCLC) patients, and biomarkers for the prognosis of patients receiving PD-1/PD-L1 inhibitors are urgently needed. LILRB2 (ILT4) is known as an immunosuppressive molecule and promotes the development and progression of NSCLC. However, the relationship between LILRB2 expression and immune microenvironment remains unclear in patients with lung adenocarcinoma. Methods: Expression profile and corresponding clinicopathological data of patients with lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database. TIMER 2.0 was used to investigate the relationship between LILRB2 expression and immune infiltrates, including T cell subset, macrophage and so on. Cox proportional hazard model was also performed to evaluate the role LILRB2 expression and immune infiltrations in prognostic prediction of patients with lung adenocarcinoma. Results: 515 patients with lung adenocarcinoma were included in analysis from TCGA dataset. LILRB2 expression was found to have significant negative correlation with CD8+ T cell infiltration (P = 0.0012), and positive correlation with CD4+ T cell infiltration (P < 0.001). There were also significant positive correlations between LILRB2 expression and Treg (P = 0.0083), cancer associated fibroblast (P < 0.001), monocyte (P < 0.001), M2 macrophage (P < 0.001) infiltration, which was regarded as the marker of immunosuppressive microenvironment. Notably, there were also significant association between the expression of LILRB2 and PD-1 (P < 0.001) and PD-L1(P < 0.001). In terms of survival analysis, high level of Treg (HR = 0.86, P = 0.03) and M2 macrophage (HR = 0.84, P = 0.017) infiltration was associated with poor prognosis of patients with lung adenocarcinoma. However, the level of CD8+T cell (HR = 0.93, P = 0.298), CD4+ T cell (HR = 0.933, P = 0.321), and LILRB2 expression (P = 0.56) was not associated with the survival of patient with lung adenocarcinoma. Conclusions: The overexpression of LILRB2 is significantly correlated with immunosuppressive immune infiltration and microenvironment in lung adenocarcinoma and might be the potential predictive biomarkers for the PD-1/PD-L1 inhibitors.

scholarly journals Identification and validation of a novel immune-related signature associated with macrophages and CD8 T cell infiltration predicting overall survival for hepatocellular carcinoma

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Junyu Huo ◽  
Liqun Wu ◽  
Yunjin Zang
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Roc Curves ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
Cell Infiltration ◽  
Immune Gene ◽  
Immune Genes ◽  
T Cell Infiltration

Abstract Background Although the effects of macrophages and CD8 T cell infiltration on clinical outcome have been widely reported, the association between immunity-associated gene with them for hepatocellular carcinoma (HCC) remains unclear. Materials and methods The ssGSEA served for quantifying the macrophages as well as CD8 T cell infiltration in the HCC samples obtained from TCGA database. Kaplan–Meier (KM) survival assay was used to determine the associations between macrophages and CD8 T cell infiltration with OS. LASSO Cox regressive method assisted in developing an immune gene signature as well as building a risk score. The performance was evaluated by the time-dependent ROC together with the KM survival analysis. The ICGC database were adopted for external verification. CIBERSORT was applied to the correlation analysis on the immune-related signature and the immunocyte infiltration. GSEA were employed exploring the underlying molecular mechanisms. Results Increased CD8+ T cell infiltration was associated with longer OS, whereas a greater infiltration of macrophages was related to shorter OS. There were 398 differential expression genes (DEGs) between the high- and low infiltration groups with the “edgeR” package. An prognostic signature consisted of 10 immune genes was built in TCGA and examined in ICGC. The uniform cutoff (0.927) was adopted for separating sufferers into the high-risk (HR) and low-risk (LR) groups. The ROC curves revealed that the AUC data for this signature predicting 1, 2, 3, 4 and 5 year were all above 0.7 in both TCGA and ICGC cohort and patients in the HR group exhibited an evidently weaker prognostic results compared with the LR group. The HR group presented evidently greater Tregs and Macrophage M0 relative to the LR group, whereas the LR group saw the enrichment of CD8 T cells. Conclusion The immune signature associated with macrophages as well as CD8 T cell infiltration has reliable prognostic and predictive value for HCC patients.

Abstract 4303: Heme Oxygenase 1 Expression in Dendritic Cells Drives Cd4+ T Cell Activation in Transplantation Atherosclerosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Annemarie M Noordeloos ◽  
C Cheng ◽  
E van Deel ◽  
D Tempel ◽  
M L Simoons ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Heme Oxygenase 1 ◽  
Cell Ratio ◽  
Mhc Ii ◽  
T Cell Infiltration ◽  
T Cell Priming

Although over-expression of heme oxygenase-1 (HO-1) attenuates transplantation arteriosclerosis, the mechanism by which HO-1 exerts its protective effect remains unclear. In order to investigate the effect of HO-1 expression specifically in the dendritic cell (DC) in the context of transplantation atherosclerosis, we studied the effect of HO1-deficient versus wildtype (WT) DCs on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. At day 0 C57bl6 mice received either WT (N=7) or HO1-knockout DCs (N=7) pre-sensitized with Balb/c splenocytes lysate. At day 10 an allogenic aorta segment derived from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice. 14 days post transplantation, the grafts were harvested and analyzed by imumnohistology. Adoptive transfer of HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 versus 38428 μm2 P<0.05). HO-1 deficient DCs also increased medial thickeness (15936 versus 12034 μm2 P<0.05), reduced intimal VSMCs content (46 versus 75% P<0.05) and resulted in more prominent medial cell infiltration (461 versus 232 μm2 P<0.05). In the transplanted aorta of the with HO-1 nullizygous DCs treated recipient group, an increase in CD4+ T-cell infiltration (9.5 versus 0.2% in WT P<0.05) and IgG deposition, concomitant to a decrease of CD8+ T cell infiltration (8.1 versus 14.3%, P<0.05) was observed. In line with these observations, in vitro analysis of HO-1 deficiency in DC function showed an increased priming potential for CD4+ T cells, thereby increasing the CD4+/CD8+ T cell ratio. Increased efficiency in CD4+ T cell priming by HO-1 deficient DCs was facilitated by a higher cell surface level of MHC II. Further studies indicated that HO-1 deficiency increased STAT1 phosphorylation, thereby enhancing CIITA gene expression that lead to increased MHC II levels on the DCs cell surface. HO-1 deficiency in dendritic cells increases vascular cell infiltration with a higher CD4+/CD8 T-cell ratio in vascular allografts resulting in an augmented form of transplantation arteriosclerosis. This effect is facilitated by a STAT1-CIITA-MHCII dependent intracellular pathway.

CD8 + T Cell Infiltration Predicts Chemoradiosensitivity in Nasopharyngeal or Oropharyngeal Cancer

2020 ◽  
Vol 131 (4) ◽  
Author(s):  
Toshihiko Kawaguchi ◽  
Takeharu Ono ◽  
Fumihiko Sato ◽  
Akihiko Kawahara ◽  
Tatsuyuki Kakuma ◽  
...  
Keyword(s):  
T Cell ◽  
Oropharyngeal Cancer ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

Abstract 760: Heme Oxygenase-1 expression in Dendritic Cells determines the Outcome of Transplantation Arteriosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Annemarie Noordeloos ◽  
Elza van Deel ◽  
Denise Hermes ◽  
Maarten L Simoons ◽  
Dirk J Duncker ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Heme Oxygenase ◽  
T Cell Activation ◽  
Neointimal Hyperplasia ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Heme Oxygenase 1 ◽  
T Cell Infiltration ◽  
Mhcii Expression

Introduction: Although expression of heme oxygenase-1 (HO1) attenuates transplantation arteriosclerosis, the mechanism by which HO1 exerts its protective effect remains unclear. We studied the effect of HO1-deficient vs. wildtype (WT) dendritic cells (DCs) on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. Methods: At day 0 C57bl6 mice received either WT (n=6) or HO1-knockout DCs (n=6) pre-sensitized with Balb/c splenocytes lysate to accelerate the development of arteriosclerosis. At day 10 an aorta segment from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice.14 days after transplantation allografts were excised and processed for immunohistochemical analysis. Results: HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 vs. 46114μm 2 P<0.05) and incidence of intima formation (83 vs. 50% in WT DC). HO1 deficient DCs also increased medial thickeness (15936 vs.12034 μm 2 P<0.05) and intimal VSMCs content (76 vs. 46% P<0.05) and resulted in more prominent medial cell infiltration (461μm 2 vs. 232μm 2 P<0.05). Although HO1 deficient and WT DCs could be detected in allografts, HO1-nullizygous DCs induced an increase in CD4+ T-cell infiltration (9.5 vs. 0.1% in WT P<0.05) concomitant to a decrease of CD8+ T cell infiltration (8 vs.14%, P<0.05). In line with these observations Affymetrix microarray analysis confirmed that HO1 deletion in DCs was associated with a significant downregulation of MHCII-H2A expression (associated with CD4+T-cell activation) and induction of inhibitors of MHCII expression (including IK protein) whereas MHC I expression remained unchanged. Conclusions: HO1 expression in dendritic cells increases vascular cell infiltration with a higher CD8+/CD4+ T-cell ratio by stabilizing MHCII expression in vascular allografts resulting in inhibition of neointima formation and hence improved allograft survival.

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