Exploration of exhausted CD8 T cell markers to predict response to immune checkpoint inhibitor therapy for hepatocellular carcinoma
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PROVIDER: PRJNA591358 | ENA |
REPOSITORIES: ENA
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Project description:This study sought to identify transcriptomic and protein markers of T cell exhaustion that may predict response to anti-program cell death-1 (anti-PD-1) / anti-PD-L1-based ICI therapy for patients with advanced/metastatic hepatocellular carcinoma (HCC).
2021-05-18 | GSE140901 | GEO
Project description:BackgroundReversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy.ObjectivesThe aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC).MethodsImmune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining.ResultsHCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8+LAG3+ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy.ConclusionsCD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.
| S-EPMC8339511 | biostudies-literature
Project description:Fresh human breast tumor tissue was dissociated into single cells and viably frozen. Patient samples were annotated as having an ""exhausted"" or ""non-exhausted"" immune environment based on CyTOF characterization of T cell phenotypes (Wagner et al, Cell 2019). 14 samples (7 exhausted, 7 non-exhausted) were selected for scRNA-seq (without prior cell type enrichment) with the goal to compare the two immune environment types and to comprehensively characterize exhaustion-associated features of the tumor microenvironment.
2023-08-25 | E-MTAB-10607 | biostudies-arrayexpress
Project description:Hypoxia promotes an aggressive tumor phenotype with increased genomic instability, partially due to downregulation of DNA repair pathways. However, in addition to DNA repair, genome stability is also controlled by cell cycle checkpoints. An important issue is therefore whether hypoxia also can alter the DNA damage cell cycle checkpoints. Here, we show that hypoxia (24h 0.2% O2) alters the expression of several G2 checkpoint regulators, as examined by microarray gene expression analysis and immunoblotting of U2OS cells. While some of the changes reflected hypoxia-induced inhibition of cell cycle progression, flow cytometric bar-coding analysis of individual cells showed that the levels of several G2 checkpoint regulators were reduced in G2 phase cells after hypoxic exposure, in particular cyclin B1. These effects were accompanied by decreased Cyclin dependent kinase (CDK) activity in G2 phase cells after hypoxia. Furthermore, cells pre-exposed to hypoxia showed a longer G2 checkpoint arrest upon treatment with ionizing radiation. Similar results were found following other hypoxic conditions (~0.03 % O2 20h and 0.2% O2 72h). These results demonstrate that the DNA damage G2 checkpoint can be altered as a consequence of hypoxia, and we propose that such alterations may influence the genome stability of hypoxic tumors. We measured gene expression changes in U2OS cells after treatment with 0.2% hypoxia for 24 hours. The data were used in the exploration of hyopxia induced alterations in the G2 checkpoint.
2016-01-04 | E-GEOD-70530 | biostudies-arrayexpress
Project description:Significant heterogeneity exists within the tumor infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted but activated (Tex/act) subpopulations critical to the improvement of therapeutic approaches. To investigate mechanisms associated with Tex/act cells, we sorted and performed transcriptional profiling of CD8+ tumor infiltrating lymphocytes (TIL) coexpressing the exhaustion markers PD-1 and TIM-3, from large volume melanoma tumors. We additionally performed immunologic phenotyping and functional validation, including at the single cell level, to identify potential mechanisms that underlie their dysfunctional phenotype. We identified novel dysregulated pathways in CD8+PD-1+TIM-3+ cells that have not been well studied in TIL; these include bile acid and peroxisome pathway-related metabolism, and mammalian target of rapamycin (mTOR) signaling pathways, which are highly correlated with immune checkpoint receptor expression. Through bioinformatic integration of immunophenotypic data and network analysis, we propose unexpected targets for therapies to rescue the immune response to tumors in melanoma.
2023-12-06 | GSE230864 | GEO
Project description:Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1-low and TOX-low, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells was uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes.
2021-04-21 | GSE172400 | GEO
Project description:CTL exhaustion is driven by chronic antigen stimulation and is characterized by specific molecular, phenotypic and functional changes. Reversing CTLs exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. However, the therapeutic effects of ICB varies among patients and cancer types. Ibrutinib, a potent BTK inhibitor, is reported that it improved T cell function in ibrutinib long-term treated chronic lymphocytic leukemia patients. However, the mechanism remains unclear. We hypothesized ibrutinib can directly act on CD8+ T cells and reinvigorates exhausted CTLs. To test this, we generated in vitro exhausted OT-I cells as previously described (Zhao M et al PLoS Pathog. 16(6): e1008555) by repeatedly stimulating cells with SIINFEKL peptide. We tested the effect of ibrutinib on inhibitory receptor, exhaustion-related transcription factor expression and cytokine (IFNγ, TNFα and IL-2) production. We found that ibrutinib decreased the expression of multiple inhibitory receptors on in vitro exhausted CTL while the critical transcription factor, Tox was downregulated. The cytokine production of exhausted cells was partially improved after ibrutinib treatment. Importantly, using btk deficient mice we found the effect of ibrutinib was independent of BTK expression. To conclude, these findings suggest that ibrutinib reduces CTL exhaustion. Our study provides evidence for ibrutinib’s synergistic use with cancer immunotherapy.
2023-09-06 | GSE220433 | GEO
Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.
2008-06-16 | E-GEOD-9650 | biostudies-arrayexpress
Project description:T-cell/histiocyte rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL, due to its peculiar cellular composition (less than 10% neoplastic B-cells interspersed in a cytotoxic T-cell/histiocyte rich background). A significant percentage of THRLBCL is refractory to RCHOP-based regimens and to CAR-T therapy; thus, the development of a specific therapeutic approach for these patients still represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, using the Nanostring PanCancer Immune Profiling panel. Gene co-expression network analysis identified the predominant role of the PD-1/PD-L1 axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of as many as 48 genes related to the functional exhaustion of T-cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly candidate THRLBCL for anti-PD-1 therapy, but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we identified a subset of TCF1+ progenitor exhausted T-cells enriched in THRLBCL patients. This subset of TCF1+ exhausted T-cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti-PD-1 response in THRLBCL patients.
2022-11-09 | GSE205919 | GEO