scholarly journals Identification of Key Genes Related to CD8+ T-Cell Infiltration as Prognostic Biomarkers for Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Minjun Du ◽  
Yicheng Liang ◽  
Zixu Liu ◽  
Xingkai Li ◽  
Mei Liang ◽  
...  
Keyword(s):  
Risk Assessment ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Assessment Model ◽  
Cell Infiltration ◽  
Risk Assessment Model ◽  
T Cell Infiltration ◽  
Key Genes

BackgroundCD8+ T cells are one of the central effector cells in the immune microenvironment. CD8+ T cells play a vital role in the development and progression of lung adenocarcinoma (LUAD). This study aimed to explore the key genes related to CD8+ T-cell infiltration in LUAD and to develop a novel prognosis model based on these genes.MethodsWith the use of the LUAD dataset from The Cancer Genome Atlas (TCGA), the differentially expressed genes (DEGs) were analyzed, and a co-expression network was constructed by weighted gene co-expression network analysis (WGCNA). Combined with the CIBERSORT algorithm, the gene module in WGCNA, which was the most significantly correlated with CD8+ T cells, was selected for the subsequent analyses. Key genes were then identified by co-expression network analysis, protein–protein interactions network analysis, and least absolute shrinkage and selection operator (Lasso)-penalized Cox regression analysis. A risk assessment model was built based on these key genes and then validated by the dataset from the Gene Expression Omnibus (GEO) database and multiple fluorescence in situ hybridization experiments of a tissue microarray.ResultsFive key genes (MZT2A, ALG3, ATIC, GPI, and GAPDH) related to prognosis and CD8+ T-cell infiltration were identified, and a risk assessment model was established based on them. We found that the risk score could well predict the prognosis of LUAD, and the risk score was negatively related to CD8+ T-cell infiltration and correlated with the advanced tumor stage. The results of the GEO database and tissue microarray were consistent with those of TCGA. Furthermore, the risk score was higher significantly in tumor tissues than in adjacent lung tissues and was correlated with the advanced tumor stage.ConclusionsThis study may provide a novel risk assessment model for prognosis prediction and a new perspective to explore the mechanism of tumor immune microenvironment related to CD8+ T-cell infiltration in LUAD.

Immunogenomic classification of gastric cancer based on the tumor microenvironments expression of PD-L1 and CD8+ T-cell infiltration.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16578-e16578
Author(s):  
Yu Chen ◽  
Gang Chen ◽  
Jia-ni Xiong ◽  
Bin Lan ◽  
Xuan Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Type I ◽  
T Cell Infiltration ◽  
Genetic Features

e16578 Background: Previous data has shown that a positive response to immunotherapy usually relies on active interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). The aim of this study was to classify gastric cancer (GC) subsets based on the TME immune status according to the expression of PD-L1 and infiltration of CD8+ T cells. Methods: One hundred and eighty-six tumor tissue from gastric cancer patients with a curative D2 gastrectomy were examined for evaluating PD-L1 and CD8+ T cells status using histopathologic analysis. The molecular characteristics of 289 GC samples in TCGA network were further analyzed to distinguish the genetic features of four immune subtypes depending on the presence of PD-L1/CD8+T cell. Results: GC samples were categorized into four types, type I (CD8+/PD-L1+, 60.3%), II (CD8-/PD-L1-, 11.8%), III (CD8-/PD-L1+, 0%), and IV (CD8+/PD-L1-, 27.9%), basing on PD-L1/CD8 expression. The PD-L1 expressing level was geographically associated with the intensity of CD8+ T cell infiltration which was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.003 and p = 0.006). Distinct patterns of genetic profile were described in four types of GC from TCGA database. Type I and III which PD-L1 were overly expressed had comparatively higher MSI and TMB, with EBV mainly enriched in Type I, whereas CIN was more likely to occur in PD-L1 aberrant types II and IV. SNV analysis illustrated higher gene mutations in oncogenes (PIK3CA and ERBB2), and in DNA damage repair related pathway, such as PRKDC, ATM, and SWI/SNF complexes (e.g. ARID1A) in Type I. However, TP53 mutations tend to enrich in Type II and IV. Similar results were obtained by transcriptome analysis. Conclusions: The genetic features of four immune subtypes proof that PD-L1 and CD8+ T cells status are reasonable immunogenomic classification of gastric cancer. SNV analysis prompts a potential mechanism for effectiveness of immunotherapy in Type I patients. Overall, the results may be useful for the development of clinical treatments for the blockade of immune checkpoints.

scholarly journals Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

2019 ◽  
Vol 316 (6) ◽  
pp. H1480-H1494 ◽  
Author(s):  
Maria M. Xu ◽  
Antoine Ménoret ◽  
Sarah-Anne E. Nicholas ◽  
Sebastian Günther ◽  
Eric J. Sundberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Antigen Recognition ◽  
Cell Infiltration ◽  
Antigen Specificity ◽  
Effector Cells ◽  
T Cell Infiltration

Effector CD8 T cells infiltrate atherosclerotic lesions and are correlated with cardiovascular events, but the mechanisms regulating their recruitment and retention are not well understood. CD137 (4–1BB) is a costimulatory receptor induced on immune cells and expressed at sites of human atherosclerotic plaque. Genetic variants associated with decreased CD137 expression correlate with carotid-intimal thickness and its deficiency in animal models attenuates atherosclerosis. These effects have been attributed in part to endothelial responses to low and disturbed flow (LDF), but CD137 also generates robust effector CD8 T cells as a costimulatory signal. Thus, we asked whether CD8 T cell-specific CD137 stimulation contributes to their infiltration, retention, and IFNγ production in early atherogenesis. We tested this through adoptive transfer of CD8 T cells into recipient C57BL/6J mice that were then antigen primed and CD137 costimulated. We analyzed atherogenic LDF vessels in normolipidemic and PCSK9-mediated hyperlipidemic models and utilized a digestion protocol that allowed for lesional T-cell characterization via flow cytometry and in vitro stimulation. We found that CD137 activation, specifically of effector CD8 T cells, triggers their intimal infiltration into LDF vessels and promotes a persistent innate-like proinflammatory program. Residence of CD137+ effector CD8 T cells further promoted infiltration of endogenous CD8 T cells with IFNγ-producing potential, whereas CD137-deficient CD8 T cells exhibited impaired vessel infiltration, minimal IFNγ production, and reduced infiltration of endogenous CD8 T cells. Our studies thus provide novel insight into how CD137 costimulation of effector T cells, independent of plaque-antigen recognition, instigates their retention and promotes innate-like responses from immune infiltrates within atherogenic foci. NEW & NOTEWORTHY Our studies identify CD137 costimulation as a stimulus for effector CD8 T-cell infiltration and persistence within atherogenic foci, regardless of atherosclerotic-antigen recognition. These costimulated effector cells, which are generated in pathological states such as viral infection and autoimmunity, have innate-like proinflammatory programs in circulation and within the atherosclerotic microenvironment, providing mechanistic context for clinical correlations of cardiovascular morbidity with increased CD8 T-cell infiltration and markers of activation in the absence of established antigen specificity. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/effector-cd8-t-cells-seed-atherogenic-foci/ .

scholarly journals Global pattern of CD8+ T cell infiltration and exhaustion in colorectal cancer predicts cancer immunotherapy response

2020 ◽  
Author(s):  
Sun Tian ◽  
Fulong Wang ◽  
Rongxin Zhang ◽  
Gong Chen
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Global Pattern ◽  
Cell Exhaustion ◽  
T Cell Infiltration

Abstract MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. We used gene expression data of 454 samples (MSI=131, MSI-L=23, MSS=284, Unknown=16) and developed a method TMEPRE that models colorectal cancer specific signature of CD8+ T cell infiltration and CD8+ T cell exhaustion states. TMEPRE showed predictive power in three datasets of anti-PD1 treated patients(p=0.056, 0.115, 0.003). CD8+ T cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection(p=0.048, 0.001). Global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characters that can benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed no sufficient amount of tumor infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signature of myeloid-derived suppressor cells in colorectal cancer.

scholarly journals Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive and resident memory T cell states

2020 ◽  
Author(s):  
Victor Tkachev ◽  
James Kaminski ◽  
E. Lake Potter ◽  
Scott N. Furlan ◽  
Alison Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cell ◽  
Transcriptomic Analysis ◽  
Cell Infiltration ◽  
Cell Transplant ◽  
Gi Tract ◽  
Tissue Invasion ◽  
T Cell Infiltration

ABSTRACTOne of the central challenges in the field of allo-immunity is deciphering the mechanisms driving T cells to infiltrate and subsequently occupy target organs to cause disease. The act of CD8-dominated T cell infiltration is critical to acute graft-versus-host disease (aGVHD), wherein donor T cells become activated, tissue-infiltrating and highly cytotoxic, causing wide-spread tissue damage after allogeneic hematopoietic stem cell transplant (allo-HCT). However, in human and non-human primate studies, deconvolving the transcriptional programs of newly recruited relative to resident memory T cells in the gastrointestinal (GI) tract has remained a challenge. In this study, we combined the novel technique of Serial Intravascular Staining (SIVS) with single-cell RNA-Seq (scRNA-seq) to enable detailed dissection of the tightly connected processes by which T cells first infiltrate tissues and then establish a pathogenic tissue residency program after allo-HCT in non-human primates. Our results have enabled the creation of a spatiotemporal map of the transcriptional drivers of CD8 T cell infiltration into the primary aGVHD target-organ, the GI tract. We identify the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphdepletion-driven T cell infiltration. The donor CD8 T cells that infiltrate the GI tract demonstrate a highly activated, cytotoxic phenotype while simultaneously rapidly developing canonical tissue-resident memory (TRM) protein expression and transcriptional signatures, driven by IL-15/IL-21 signaling. Moreover, by combining SIVS and transcriptomic analysis, we have been able to work backwards from this pathogenic TRM programing, and, for the first time, identify a cluster of genes directly associated with tissue invasiveness, prominently including specific chemokines and adhesion molecules and their receptors, as well as a central cytoskeletal transcriptional node. The clinical relevance of this new tissue invasion signature was validated by its ability to discriminate the CD8 T cell transcriptome of patients with GI aGVHD. These results provide new insights into the mechanisms controlling tissue infiltration and pathogenic CD8 TRM transcriptional programing, uncovering critical transitions in allo-immune tissue invasion and destruction.One sentence summaryFlow cytometric and transcriptomic analysis reveals coordinated tissue-infiltration and tissue-residency programs driving gastrointestinal aGVHD.

Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3061-3061 ◽  
Author(s):  
Mark Selby ◽  
John Engelhardt ◽  
Li-Sheng Lu ◽  
Michael Quigley ◽  
Changyu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cell Infiltration ◽  
Preclinical Models ◽  
Concurrent Treatment ◽  
T Cell Infiltration ◽  
Synergistic Antitumor Activity

3061 Background: Interaction of immune checkpoint molecules PD-1 and CTLA-4 and their respective ligands attenuates antitumor T cell responses. In clinical studies, PD-1 blocking antibody (Ab) nivolumab (BMS-936558) or the CTLA-4 blocking Ab ipilimumab result in durable responses in multiple human malignancies. We describe the evaluation of concurrent treatment with anti-PD-1 and anti-CTLA-4 mAbs in preclinical models. Methods: Antitumor activity of treatment with murine homologs of anti-PD-1 (4H2-mIgG1) and anti-CTLA-4 (9D9-mIgG2b) was evaluated in MC38, a murine colon adenocarcinoma model. The effects of concurrent treatment on T cell infiltration of tumors, tumoral expression of PD-L1 and cytokine levels were explored. The preclinical safety profile of concurrent nivolumab + ipilimumab was assessed in a cynomolgus macaque model. Results: Concurrent treatment of MC38 tumors with 4H2-mIgG1 + 9D9-mIgG2b (10 mg/kg Q3d x 3) results in synergistic antitumor activity whereas efficacy with sequential dosing was similar to either agent alone. With concurrent treatment, dose reductions of one Ab relative to a fixed dose of the other resulted in retention of some antitumor activity. Anti-PD-1 enhanced CD8+ T cell infiltration of MC38 tumors and increased tumor PD-L1 expression. Anti-CTLA-4 treatment increased intratumoral CD8+ T cells and reduced intratumoral T regulatory cells. While concurrent treatment did not result in further increases in T cell infiltration, it increased expression of intratumoral cytokines. Anti-PD-1 resulted in down regulation of cell surface and intracellular levels of PD-1 in CD8+ T cells. In cynomolgus macaques, concurrent nivolumab + ipilimumab resulted in dose-dependent gastrointestinal toxicities (diarrhea; body weight loss) not observed in earlier cynomolgus studies with nivolumab and rarely with ipilimumab. These preclinical observations provided the rationale for a dose escalation trial (NCT01024231) of combined nivolumab + ipilimumab in advanced melanoma. Conclusions: Concurrent treatment with anti-PD-1/anti-CTLA-4 resulted in synergistic antitumor activity in preclinical models and supports the evaluation of the combination in clinical studies.

scholarly journals DNA Methylation based glioblastoma subclassification is related to tumoral T cell infiltration and patient survival

2020 ◽  
Author(s):  
Joost Dejaegher ◽  
Lien Solie ◽  
Zoé Hunin ◽  
Raf Sciot ◽  
David Capper ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Methylation Pattern ◽  
Response To Therapy ◽  
Cell Infiltration ◽  
Mesenchymal Tumors ◽  
T Cell Infiltration

Abstract Background Histologically classified Glioblastomas (GBM) can have different clinical behavior and response to therapy, for which molecular subclassifications have been proposed. We evaluated the relationship of epigenetic GBM subgroups with immune cell infiltrations, systemic immune changes during radiochemotherapy and clinical outcome. Methods 450K genome-wide DNA methylation was assessed on tumor tissue from 93 patients with newly diagnosed GBM, treated with standard radiochemotherapy and experimental immunotherapy. Tumor infiltration of T cells, myeloid cells and PD-1 expression were evaluated. Circulating immune cell populations and selected cytokines were assessed on blood samples taken before and after radiochemotherapy. Results Forty-two tumors had a mesenchymal, 27 a RTK II, 17 a RTK I and 7 an IDH DNA methylation pattern Mesenchymal tumors had the highest amount of tumor-infiltrating CD3+ and CD8+ T cells and IDH tumors the lowest. There were no significant differences for CD68+ cells, FoxP3+ cells and PD-1 expression between groups. Systemically, there was a relative increase of CD8+ T cells and CD8+ PD-1 expression and a relative decrease of CD4+ T cells after radiochemotherapy in all subgroups except IDH tumors. Overall survival was the longest in the IDH group (median 36 months), intermediate in RTK II tumors (27 months) and significantly lower in mesenchymal and RTK I groups (15.5 and 16 months respectively). Conclusions Methylation based stratification of GBM is related to T cell infiltration and survival, with IDH and mesenchymal tumors representing both ends of a spectrum. DNA methylation profiles could be useful in stratifying patients for immunotherapy trials.

PAX5 haploinsufficiency induces low T cell infiltration in the cancer microenvironment via reduced chemokines

2021 ◽  
Vol 21 ◽  
Author(s):  
Lei Wang ◽  
Xue Liang ◽  
Mi Liang ◽  
Dang Li ◽  
Jia Gu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Gene Editing ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Loss Of Function ◽  
Wild Type ◽  
T Cell Infiltration ◽  
Wild Type Control

Aims: To investigate the effects of PAXT mutations on tumor immunity. Background: Loss of function of PAX5 plays a key role in PAX5 mutation tumor. Objective: PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape, but there was no report about mechanisms of PAX5 mutation inducing tumor immunological escape. Method: We constructed the PAX5 haplodeletion A20 cell lines using gene-editing technology, built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on T cells and chemokines in the tumor microenvironment (TME). Result: Our results from different methods indicated percentages of CD3+ CD4+ T cells and CD3+ CD8+ T cells in TME of PAX5 haplodeletion clones decreased significantly compared with that of PAX5 wild type control. Several chemokines, such as Ccl2, Ccl4, Cxcl9 and Cxcl10, in TME of PAX5. Conclusion: Our study showed that PAX5 haploinsufficiency induced low T cell infiltration in TME using decreased chemokines.

Hot clear cell renal cell carcinoma immune status: Illusion or reality?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16575-e16575
Author(s):  
Xingang Bi ◽  
Yi Lu ◽  
Xinyu Bi ◽  
Zhiwen Luo
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Prognostic Model ◽  
Immune Status ◽  
Cd8 T Cell ◽  
Cytolytic Activity ◽  
Cell Infiltration ◽  
Cell Renal Cell Carcinoma ◽  
T Cell Infiltration

e16575 Background: High tumor mutation burden (TMB) and increased CD8+ T cells infiltration are associated with positive ICIs response in many solid cancers. But non-responsive clear cell renal cell carcinoma (ccRCC) features modest TMB, high CD8+ T-cell infiltration but poor survival. Costimulatory molecules confer immune cell activation within the immune response. Therefore, we aimed to investigate ccRCC’s unique immune environment related prognosis and ICIs’ sensitivity from the aspect of co-stimulation alteration. Methods: We analyzed the combined ccRCC cohort of 844 patients’ RNA sequencing data, from two sources: One ccRCC group (533 patients) was from The Cancer Genome Atlas KIRC (TCGA-KIRC), and the validation group (311 patients) was from an ICIs treated clinical trial. Univariate, LASSO, and multivariate Cox regression analyses were used to identify overall survival-related costimulatory genes, which were used to build an immune prognostic model (IPM) stratifying survival risk level in ccRCC. Comprehensive bioinformatics discovered the relationship between immune status, ICIs’ sensitivity with IPM’ prognosis risk. Results: The survival related co-stimulatory genes were identified in 533 ccRCC patients to construct an immune prognostic model (IPM) to differentiate patients with a low or high risk of poor survival (AUC = 0.75). Functional enrichment analysis showed T cell homeostasis represented the major function alteration related to IPM risk score ( P< 0.05). ICIs clinical trial cohort validated the IPM’s moderate prediction performance for the ICIs response ( P= 0.028), for IPM-high risk patients are more likely to be resistant to ICIs. The high-risk group had higher CD8 + T cell infiltration, higher TMB, and higher cytolytic activity, while such a hot immune status was an illusion concealing the T cells homeostasis alteration with the increased proportion of dysfunctional CD8+ and CD4+ T cells, immunosuppressive cells (i.e., iT-regs, nT-regs, and CAFs) in IPM-high risk, this kind of refractory ccRCC subtype. Conclusions: Baseline CD8 + T cell infiltration, TMB, and cytolytic activity could not predict response to ICI in the ccRCCs, and hot tumor immune status represented by CD8+T cells in resistant ccRCC is an illusion concealing T cells homeostasis alteration. T cells homeostasis could provide critical insights into immunogenomic mechanisms contributing to the immunotherapy sensitivity in ccRCC. Our five-gene based IPM tested easily by PCR, was clinically accessible, cheap and useful for indicating refractory ccRCCs to undergo ICIs.

scholarly journals Dihydroartemisinin broke immune evasion through YAP1/JAK1/STAT1, 3 pathways to enhance anti-PD-1 therapy in hepatocellular carcinoma

2021 ◽  
Author(s):  
Qing Peng ◽  
Shenghao Li ◽  
Xinli Shi ◽  
Yinglin Guo ◽  
Liyuan Hao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Immune Evasion ◽  
Cd8 T Cells ◽  
Liver Tumor ◽  
Therapeutic Strategy ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Tumor Tissues

The efficacy of anti-PD-1 therapy is not as expected in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) was overexpressed and activated in HCC. This study aimed to investigate the potential mechanism and inhibitor of YAP1 on immune evasion, and promote anti-PD-1 therapy in HCC. Here, we showed that dihydroartemisinin (DHA), an FDA approved drug, directly suppressed YAP1 expression, leading to break immune evasion in liver tumor niche, characterized by decreased PD-L1 in liver tumor cells and increased CD8+ T cell infiltration. Mechanismly, YAP1 is not only directly related to PD-L1, but also involved in activating the JAK1/STAT1, 3 pathways. Moreover, Yap1 knockout elevated CD4+ and CD8+ T cells in liver tumor niche of Yap1LKO mice. Consistently, verteporfin, YAP1 inhibitor, decreased TGF-β in liver tumor niche and exhausted CD8+ T cells in spleen. Furthermore, DHA combined with anti-PD-1 treatment promoted CD4+ T cell infiltration in the spleen and CD8+ T cells in tumor tissues. Thus, we provide a new combined therapeutic strategy for anti-PD-1 with DHA, a potent YAP1 inhibitor, in HCC.

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