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 Global Pattern of CD8+ T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Sun Tian ◽  
Fulong Wang ◽  
Rongxin Zhang ◽  
Gong Chen
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cell Infiltration ◽  
Specific Method ◽  
T Cell Exhaustion ◽  
Global Pattern ◽  
Cell Exhaustion ◽  
T Cell Infiltration

Background: The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response.Methods: We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8+ T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8+ T cells in different exhaustion states.Results: 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). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer.Conclusion: TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8+ T-cell infiltration and CD8+ T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8+ T cells or terminal exhaustion of CD8+ T cells need different treatment strategies.

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 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.

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 342 Combining enadenotucirev and nivolumab increased tumour immune cell infiltration/activation in patients with microsatellite-stable/instability-low metastatic colorectal cancer in a phase 1 study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A368-A369
Author(s):  
David Krige ◽  
Marwan Fakih ◽  
Lee Rosen ◽  
Ding Wang ◽  
Wael Harb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Institutional Review Board ◽  
Cell Infiltration ◽  
Link Type ◽  
T Cell Infiltration ◽  
Institutional Review

BackgroundMicrosatellite-stable (MSS) and instability-low (MSI-L) metastatic colorectal cancer (mCRC) are typically characterised as ”immune-excluded/desert” tumour microenvironments lacking T-cell infiltration. Anti-PD-1 monotherapy has little clinical benefit in MSS/MSI-L mCRC1 and knowledge of the effects of PD-1 inhibition on T-cell activation/infiltration in this population is limited. Novel combination therapies to overcome anti-PD-1 resistance are required. SPICE is a multicentre, open-label, phase 1 study of the tumour-selective chimeric Ad11/Ad3 group B oncolytic adenovirus enadenotucirev plus nivolumab in patients with metastatic/advanced epithelial tumours refractory to standard therapy. Preliminary data from patients with MSS/MSI-L mCRC demonstrated a median overall survival of 14 months, manageable tolerability and intratumoural T-cell infiltration.2 Here we characterise the immunological effects of tumour re-engineering with enadenotucirev in combination with nivolumab in patients with MSS/MSI-L mCRC.MethodsPatients received increasing doses and/or cycles of intravenous enadenotucirev followed by up to 8 cycles of nivolumab as previously described.2 Wherever possible, pre- and post-treatment (~5 weeks post-first enadenotucirev) biopsies were collected; samples were analysed using immunohistochemistry and automated image analysis. Peripheral blood mononuclear cell immunophenotyping (multiparameter flow cytometry) and serum cytokines were assessed at multiple times.Results43 patients with mCRC were treated (86% MSS/MSI-L; 14% unknown). Among the 13 patients (12/13 MSS/MSI-L; 1/13 unknown) with matched biopsies, 11 had increased intratumoural and stromal CD8+ T-cell infiltration in post-treatment biopsies (median [Q1-Q3] fold changes 6.5× [1.5–25.4] and 1.9× [1.5–3.9], respectively; figure 1). CD4+ T-cell density increased in 10/13 patients and 8/13 patients had increased proportions of PD-L1+ immune cells. Increases in CD8 T-cell proliferation (Ki67; 7/9 patients) and cytolytic activity (Granzyme B; 7/13 patients) markers were seen. 4/13 patients converted from a ”desert” to an ”inflamed” immune phenotype (pathologist scored CD8/pan-cytokeratin staining). Immunophenotyping showed trends towards increased T-cell activation (CD38+ and HLA-DR+ CD8+ T cell populations) post-treatment (9/10 patients), including in one patient who had only received enadenotucirev prior to sampling. Persistent increases in inflammatory cytokines (IFNγ, IL-12p70, IL-17a) were seen in two patients from ~Day 15, including one who achieved a sustained objective response.Abstract 342 Figure 1Tumour immune cell infiltration following treatment with enadenotucirev plus nivolumabConclusionsThese data show that intravenous enadenotucirev plus nivolumab can induce immune infiltration/activation within MSS/MSI-L mCRC. These encouraging findings suggest that immune activation can be achieved even in ”immune-excluded/desert” tumours. SPICE has been closed following completion of dose-escalation. Efforts are now focused on the development of next-generation variants of enadenotucirev designed to further re-programme the tumour microenvironment by expressing immune-enhancer transgenes (T-SIGn vectors); these studies are ongoing (NCT04830592, NCT04053283, NCT03852511).AcknowledgementsThis study was funded by PsiOxus Therapeutics Limited and Bristol Myers Squibb. Medical writing support: Lola Parfitt, MRes, of PsiOxus Therapeutics Limited.Trial RegistrationEudraCT number2017-001231-39NCT number: NCT02636036ReferencesKawazoe A, Kuboki Y, Shinozaki E, et al. Multicenter phase I/II trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP trial). Clin Cancer Res 2020;26:5887–5894.Fakih M, Wang D, Harb W, et al. SPICE: a phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase. Ann Oncol 2019:30(suppl_5):v252.Ethics ApprovalThe study was approved by the WCG Institutional Review Board (study approval number 20152656), UCLA Institutional Review Board (study approval number IRB#15-002010), Vanderbilt Institutional Review Board (study approval number IRB #171453) and Henry Ford Institutional Review Board (study approval number IRB #10349).

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.

scholarly journals Intrinsic β-catenin signaling suppresses CD8+ T-cell infiltration in colorectal cancer

2019 ◽  
Vol 115 ◽  
pp. 108921 ◽  
Author(s):  
Junli Xue ◽  
Xuetao Yu ◽  
Liqiong Xue ◽  
Xiaoxiao Ge ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4671-4678 ◽  
Author(s):  
Ji-Yuan Zhang ◽  
Zheng Zhang ◽  
Xicheng Wang ◽  
Jun-Liang Fu ◽  
Jinxia Yao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Specific Memory ◽  
Memory Cd8 T Cell

Abstract The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8+ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-γ production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8+ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs.

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